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{{Infobox protein family|Symbol=SNAP|Name=Soluble NSF Attachment Protein|image=Crystal Structure of the Vesicular Transport Protein Sec17.jpg|caption=Sec17 is yeast is an ortholog of the human SNAP and acts in membrane fusion of vesicles. SNAP complexes with SNARE and NSF to form 20S particles.|Pfam=PF14938|Interpro=IPR000744|PROSITE=PDOC50192, PDOC50892|CDD=cd15832}}
{{Infobox protein family|Symbol=SNAP|Name=Soluble NSF Attachment Protein|image=Crystal Structure of the Vesicular Transport Protein Sec17.jpg|caption=Sec17 is yeast is an ortholog of the human SNAP and acts in membrane fusion of vesicles. SNAP complexes with SNARE and NSF to form 20S particles.|Pfam=PF14938|Interpro=IPR000744|PROSITE=PDOC50192, PDOC50892|CDD=cd15832}}


==References==
== Function ==
The function of SNAP proteins have been primarily related to the role which the play in the assemble and disassembly of SNARE complex required for vesicle fusion events. According to the [[SNARE (protein)|SNARE hypothesis]] developed in the early 1990s, SNAP protein are localized to the membranes and are central in mediating [[Vesicle fusion|Ca<sup>2+</sup> dependent vesicle fusion]] at these these sites. SNAPs associate with the proteins of the [[SNARE (protein)|SNARE (<u>SNA</u>P <u>RE</u>ceptor)]] complex, a class of type II integral membrane protein, as well as the ATPase NSF, largely based on [[Electrostatics|electrostatic interactions]].<ref name=":0" /><ref name=":4">{{Cite journal|last=Rizo|first=Josep|date=2018-08|title=Mechanism of neurotransmitter release coming into focus: Mechanism of Neurotransmitter Release|url=https://onlinelibrary.wiley.com/doi/10.1002/pro.3445|journal=Protein Science|language=en|volume=27|issue=8|pages=1364–1391|doi=10.1002/pro.3445|pmc=PMC6153415|pmid=29893445}}</ref> The interaction of the SNAPs with [[SNARE (protein)|SNARE]]<nowiki/>s takes place before interaction of the complex with [[N-ethylmaleimide sensitive fusion protein|NSF]] (Sec18 in yeast) suggesting a sequence for the priming assembly may be necessary.<ref name=":0">{{Cite journal|last=Stenbeck|first=Gudrun|date=1 May 1998|title=Soluble NSF-attachment proteins|journal=The International Journal of Biochemistry & Cell Biology|volume=30|pages=573-577|doi=10.1016/S1357-2725(97)00064-2|via=Elsevier}}</ref> <ref name=":5">{{Cite journal|last=Sparks|first=Robert P.|last2=Arango|first2=Andres S.|last3=Starr|first3=Matthew L.|last4=Aboff|first4=Zachary L.|last5=Hurst|first5=Logan R.|last6=Rivera-Kohr|first6=David A.|last7=Zhang|first7=Chi|last8=Harnden|first8=Kevin A.|last9=Jenkins|first9=Jermaine L.|last10=Guida|first10=Wayne C.|last11=Tajkhorshid|first11=Emad|date=2019-11|title=A small-molecule competitive inhibitor of phosphatidic acid binding by the AAA+ protein NSF/Sec18 blocks the SNARE-priming stage of vacuole fusion|url=https://linkinghub.elsevier.com/retrieve/pii/S002192582030716X|journal=Journal of Biological Chemistry|language=en|volume=294|issue=46|pages=17168–17185|doi=10.1074/jbc.RA119.008865|pmc=PMC6873166|pmid=31515268}}</ref> The assembled complex which includes SNAP, [[SNARE (protein)|SNARE]], and [[N-ethylmaleimide sensitive fusion protein|NSF]] is known as the 20S complex. Some of the first proteins identified as the receptors of SNAPs were [[Syntaxin|syntaxin 1]], [[SNAP25|SNAP-25]] (synaptosome associated protein, 25kDa), and VAMP ([[synaptobrevin]]).<ref name=":9">{{Cite journal|last=Nichols|first=Benjamin J|last2=Pelham|first2=Hugh R.B|date=1998-08|title=SNAREs and membrane fusion in the Golgi apparatus|url=https://linkinghub.elsevier.com/retrieve/pii/S0167488998000445|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|language=en|volume=1404|issue=1-2|pages=9–31|doi=10.1016/S0167-4889(98)00044-5}}</ref> These proteins are contain transmembrane regions can can be found in both intracellular vesicles and as part of extracellular trafficking machinery. Figure 1 shows interactions of the vesicular and membrane [[SNARE (protein)|SNARE proteins]] with [[NSFL1C|NSF]] and SNAP in the assembly, fusion, and disassembly process that accompanies vesicle fusion events.
{{Reflist}}


Initial binding of [[N-ethylmaleimide sensitive fusion protein|NSF]] to SNAP been is likely related to interactions of the 63 [[N-terminus|N-terminal]] and 37 [[C-terminus|C-terminal]] amino acid residues of SNAP with [[N-ethylmaleimide sensitive fusion protein|NSF]] protein.<ref name=":2">{{Cite journal|last=Rice|first=Luke M|last2=Brunger|first2=Axel T|date=1999-07|title=Crystal Structure of the Vesicular Transport Protein Sec17|url=https://linkinghub.elsevier.com/retrieve/pii/S1097276500801902|journal=Molecular Cell|language=en|volume=4|issue=1|pages=85–95|doi=10.1016/S1097-2765(00)80190-2}}</ref> The interaction with SNAP stimulates the ATPase activity of the [[N-ethylmaleimide sensitive fusion protein|NSF]] when assembled into the 20S complex, and ultimately leads to [[ATP hydrolysis]] that result in the disruption of the heterooligomeric complex.<ref name=":10">{{Cite journal|last=Chen|first=Yu A.|last2=Scheller|first2=Richard H.|date=01 Feb 2001|title=SNARE-mediated membrane fusion|url=http://www.nature.com/articles/35052017|journal=Nature Reviews Molecular Cell Biology|language=en|volume=2|issue=2|pages=98–106|doi=10.1038/35052017|issn=1471-0072}}</ref> This has the potential to reduce or block [[Neurotransmission|synaptic transmission]], ultimately leading to the loss of signaling downstream. Further information on this is included in the toxicology section below.
[[Category:Membrane biology]]
[[Category:Proteins]]


While assembly of the complex can take place under only conditions where a components and a [[membrane]] is present, disassembly requires that NSF can [[ATP hydrolysis|hydrolyze ATP.]]<ref name=":0" /> Use of [[Chelation|chelating agents]], non-hydrolysable analogues of [[GTPgammaS|GTP]], or application of an [[N-Ethylmaleimide|alkylating agent N-ethylmaleimide (NEM)]], therefore, has been used to demonstrate prevention of vesicle fusion [[in vitro]].<ref name=":9" /> Blocking the assembly of the 20S complex also prevents the ATP-hydrolysis reaction from taking place at [[N-ethylmaleimide sensitive fusion protein|NSF]].


=== Limitations of the Original SNARE Theory of Vesicle Fusion ===
{{Protein-stub}}
[[File:Ca2+ dependent fusion of vesicles.png|thumb|274x274px|Fig 1. The vesicle fusion complex. The vesicle approaches the membrane and proteins including SNAP, NSF, synaptobrevin, syntaxin, and synaptotagmin SNARE proteins form the 20S SNARE Complex required for fusion. The ATPase action of NSF drives disassembly post priming of the complex. Ca<sup>2+</sup> influx due to depolarization drives vesicle fusion to the membrane and release of neurotransmitters.]]
It is important to note, however, that the [[SNARE (protein)|SNARE]] Theory of the vesicle fusion, which encompasses the action description of SNAREs, SNAP, and [[N-ethylmaleimide sensitive fusion protein|NSF]], does not completely explain all known [[vesicle fusion]] events.<ref name=":0" /> The theory was formulated by [[James Rothman]] and co-workers staring in the early 1990s and originally predicted that SNAPs and [[N-ethylmaleimide sensitive fusion protein|NSF]] recognized paired [[SNARE (protein)|vesicle-SNARE (v-SNARE)]]/ target-SNARE (t-SNARE) complexes at membranes and bound to them thus creating the 20S complex.<ref name=":9" /><ref>{{Cite journal|last=Rothman|first=James E.|date=1994-11|title=Mechanisms of intracellular protein transport|url=http://www.nature.com/articles/372055a0|journal=Nature|language=en|volume=372|issue=6501|pages=55–63|doi=10.1038/372055a0|issn=0028-0836}}</ref>

All mechanistic considerations of vesicle fusion by SNARE complexes is not fully explained by this earlier version of the theory. Specifically, for data generated experimentally in recent years lead some to question the completeness of the model. Although it was known since the 1960s that Ca<sup>2+</sup> influx was responsible for synaptic signaling, a collaboration in 1992 between [[Thomas C. Südhof|Thomas Südhof]] and [[Reinhard Jahn|Reinhardt Jahn]] tied the link between calcium, SNARE complexes and synaptic signaling. At the time, outdated considerations could not account for the rapid release of neurotransmitters into synaptic clefts, as the turnaround was thought to be limited by the rate of recycling of the SNAREs. Consensus, however, has been maintained around the participating proteins (SNAPs, NSF, SNAREs) and their function as part of membrane fusion systems across the the cell, in both synaptic and vacuolar systems including the Golgi transport .<ref name=":9" />

=== Significance in CNS Signaling ===
Further studies demonstrated that the [[ATP hydrolysis]] step occurs prior to a calcium ion mediated fusion event, and thus, that SNAP and NSF proteins initiate disassembly the 20S complex before the docking event takes place directly at the membrane. Once intracellular Ca<sup>2+</sup> achieve significantly high levels to facilitate docking, the molecular clamp protein called [[synaptotagmin]] acts in a Ca<sup>2+</sup> sensitive manner to facilitate fusion of the vesicle to the membrane.<ref name=":11">{{Cite journal|last=Hussain|first=S.|last2=Davanger|first2=S.|date=2011-09|title=The discovery of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex and the molecular regulation of synaptic vesicle transmitter release: the 2010 Kavli Prize in neuroscience|url=https://linkinghub.elsevier.com/retrieve/pii/S0306452211006324|journal=Neuroscience|language=en|volume=190|pages=12–20|doi=10.1016/j.neuroscience.2011.05.057}}</ref><ref name=":9" /> The exocytosis of neurotransmitters as regulated by Ca<sup>2+</sup> is faster kinetically than would be possible by the SNARE-recycling model alone.<ref name=":10" /><ref name=":9" /> Figure 1 summarizes the updated model of the SNARE hypothesis.

The existence of primed vesicles ready for fusion at the pre-synaptic membrane due to interactions of SNAP and NSF preceding vesicle fusion more closely predicts the mechanism of neurotransmitter release as it does not see the delay predicted by the traditional SNARE mechanism for recycling. A depolarizing current of the pre-synaptic neuron leads to the opening of [[Voltage-gated ion channel|voltage dependent ion channels]] that permit the influx of Ca<sup>2+</sup> into the cell, and then initiate the fusion of vesicles at a rate of one vesicle per 100us. <ref name=":9" />

=== Significance in Toxicology ===
[[File:Botulinum Toxin Mechanism.png|thumb|Action of botulinum toxin at the synaptic nerve terminals interferes with the assembly of the 20S SNARE complex and prevents the signaling.]]The 20S complex is a known to be target for [[Clostridium]] [[Neurotoxin|neurotoxins]] including [[Botulinum toxin|Botulinum A, C. and E]], which block synaptic transmission by disrupting the complex and preventing neurotransmitter release into the synaptic space.<ref>{{Cite journal|last=Montecucco|first=Cesare|last2=Schiavo|first2=Giampietro|date=1995-11|title=Structure and function of tetanus and botulinum neurotoxins|url=https://www.cambridge.org/core/product/identifier/S0033583500003292/type/journal_article|journal=Quarterly Reviews of Biophysics|language=en|volume=28|issue=4|pages=423–472|doi=10.1017/S0033583500003292|issn=0033-5835}}</ref> The disruption to synaptic transmission is the result of the serotype B toxins cleaving only VAMP-2/synaptobrevin-2 but not type 1 SNARE proteins. These toxins do not directly interact with SNAP but the resultant is the failure to form the 20S vesicle fusion complex.<ref name=":9" /><ref name=":11" /> Botulinum toxin impairs synaptic transmission is impaired at the neuromuscular junction due to blocking of acetyl choline release onto the endplate leading to muscle paralysis and, if left untreated, death.<ref name=":12">{{Cite journal|last=Dutta|first=ShubhaRanjan|last2=Passi|first2=Deepak|last3=Singh|first3=Mahinder|last4=Singh|first4=Purnima|last5=Sharma|first5=Sarang|last6=Sharma|first6=Abhimanyu|date=2016|title=Botulinum toxin the poison that heals: A brief review|url=http://www.njms.in/text.asp?2016/7/1/10/196133|journal=National Journal of Maxillofacial Surgery|language=en|volume=7|issue=1|pages=10|doi=10.4103/0975-5950.196133|issn=0975-5950|pmc=PMC5242063|pmid=28163472}}</ref> Poisoning by botulinum toxin generally occurs through ingestion of material contaminated with the toxin producing bacteria or absorbance of the toxin through the skin.

[[SNARE (protein)|SNARE]] complexes containing SNAP are also targets for [[Tetanus|tetanus toxin]] which likewise inhibit [[vesicle fusion]] and [[Synaptic vesicle|neurotransmitter]] release through anterograde transport of the toxin into the CNS.<ref name=":0" /><ref>{{Cite journal|last=Binz|first=Thomas|last2=Sikorra|first2=Stefan|last3=Mahrhold|first3=Stefan|date=2010-04-13|title=Clostridial Neurotoxins: Mechanism of SNARE Cleavage and Outlook on Potential Substrate Specificity Reengineering|url=http://www.mdpi.com/2072-6651/2/4/665|journal=Toxins|language=en|volume=2|issue=4|pages=665–682|doi=10.3390/toxins2040665|issn=2072-6651|pmc=PMC3153214|pmid=22069605}}</ref><ref name=":12" /> Prevention of 20S snare complex assembly due to cleaved components prevents SNAPs from interaction with the receptor proteins in a non-competitive manner.

== Genetics ==
Expression of the three SNAP proteins in mammalian is tissue dependent with [[NAPA (gene)|α-SNAP]] (33kD) and [[NAPG|γ-SNAP]] (36kD) expressed throughout the body, and [[NAPB|β-SNAP]] (34kD) primarily found in brain tissues.<ref name=":0" /> [[NAPA (gene)|α-SNAP]] and [[NAPG|β-SNAP]] share approximately 83% sequence homology and are encoded by [[NAPA (gene)|NAPA]] and [[NAPB]] on [[Chromosome 19|chromosomes 19]] and [[Chromosome 18|18]], respectively in humans.<ref name=":6">{{Cite journal|last=Andreeva|first=Alexandra V|last2=Kutuzov|first2=Mikhail A|last3=Voyno-Yasenetskaya|first3=Tatyana A|date=2006-10|title=A ubiquitous membrane fusion protein αSNAP: a potential therapeutic target for cancer, diabetes and neurological disorders?|url=http://www.tandfonline.com/doi/full/10.1517/14728222.10.5.723|journal=Expert Opinion on Therapeutic Targets|language=en|volume=10|issue=5|pages=723–733|doi=10.1517/14728222.10.5.723|issn=1472-8222}}</ref> [[NAPB|β-SNAP]] protein is encoded by the [[NAPB]] on [[chromosome 20]]. Changes in temporal expression have been observed in rodent models during embryonic development but similar changes in humans is yet to be verified. <ref name=":0" /> Expression data in the early years after discovery of the protein group in the 1990s were primarily confirmed though use of [[Western blot|Western blo]]<nowiki/>t and allowed expression of the [[Messenger RNA|mRNA]] and later [[Complementary DNA|cDNA]]. Use of [[Immunofluorescence|Immunofluorescent localization]] showed strong association of the proteins to intracellular membranes including the [[Endoplasmic reticulum|ER]] and [[Golgi apparatus|Golgi bodies]] as well as [[Vesicle (biology and chemistry)|vesicles]]. <ref name=":1">{{Cite journal|last=Whiteheart|first=Sidney W.|last2=Griff|first2=Irene C.|last3=Brunner|first3=Michael|last4=Clary|first4=Douglas O.|last5=Mayer|first5=Thomas|last6=Buhrow|first6=Susan A.|last7=Rothman|first7=James E.|date=1993-03|title=SNAP family of NSF attachment proteins includes a brain-specific isoform|url=http://www.nature.com/articles/362353a0|journal=Nature|language=en|volume=362|issue=6418|pages=353–355|doi=10.1038/362353a0|issn=0028-0836}}</ref>

Deletions in [[NAPA (gene)|α-SNAP]] gene have also been found to be lethal in utero in rodent models with ''hyh'' (hydrocephalus with hop gait) <ref>{{Cite journal|last=Chae|first=Teresa H|last2=Kim|first2=Seonhee|last3=Marz|first3=Karla E|last4=Hanson|first4=Phyllis I|last5=Walsh|first5=Christopher A|date=2004-02-01|title=The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate|url=http://dx.doi.org/10.1038/ng1302|journal=Nature Genetics|volume=36|issue=3|pages=264–270|doi=10.1038/ng1302|issn=1061-4036}}</ref> while ''hyh'' due to missense mutations lead to 40% lower levels of expression.<ref name=":7">{{Cite journal|last=Hong|first=H.-K.|last2=Chakravarti|first2=A.|last3=Takahashi|first3=J. S.|date=2004-02-10|title=From The Cover: The gene for soluble N-ethylmaleimide sensitive factor attachment protein is mutated in hydrocephaly with hop gait (hyh) mice|url=http://www.pnas.org/cgi/doi/10.1073/pnas.0308268100|journal=Proceedings of the National Academy of Sciences|language=en|volume=101|issue=6|pages=1748–1753|doi=10.1073/pnas.0308268100|issn=0027-8424|pmc=PMC341847|pmid=14755058}}</ref> The effects of the mutations develop in utero and become more sever over time, ultimately leading to worsening hydrocephalus and death. Reduced expression of [[NAPA (gene)|α-SNAP]] in ''hyh/hyh'' mice is also associated with CD4 T-cell effector cytokine deficiency. <ref name=":8">{{Cite journal|last=Miao|first=Yong|last2=Bhushan|first2=Jaya|last3=Dani|first3=Adish|last4=Vig|first4=Monika|date=2017-05-11|title=Na+ influx via Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation|url=https://elifesciences.org/articles/25155|journal=eLife|language=en|volume=6|pages=e25155|doi=10.7554/eLife.25155|issn=2050-084X|pmc=PMC5459575|pmid=28492364}}</ref>

[[Saccharomyces cerevisiae|Yeast (S. ''cerevisiae'']]) homolog of the SNAP gene known as Sec17p has 67% similarity to mammalian [[NAPA (gene)|α-SNAP]] <ref name=":0" /> or approximately 34% homology with alpha and 33% with beta.<ref name=":1" /> It has been studied based on its function in yeast vacuolar fusion.<ref name=":4" /> The lethality of the double null mutation in this animal highlights the importance of this class of proteins in intra and inter-cell communication and survival.

== Structure ==
Use of [[Transmission electron microscopy|TEM]] and [[Förster resonance energy transfer|FRET]] imaging techniques was widely applied at the beginning of the century to resolve the [[SNARE (protein)|SNARE]] complex and expanded to include SNAP proteins as well. The 20S complex ultimately forms a rod of 2.5nm width by 15nm in length that assembles along the axis of two coiled coils of interacting SNARE proteins.<ref name=":9" /><ref name=":3">{{Cite journal|last=Hohl|first=Tobias M|last2=Parlati|first2=Francesco|last3=Wimmer|first3=Christian|last4=Rothman|first4=James E|last5=Söllner|first5=Thomas H|last6=Engelhardt|first6=Harald|date=1998-11|title=Arrangement of Subunits in 20 S Particles Consisting of NSF, SNAPs, and SNARE Complexes|url=https://linkinghub.elsevier.com/retrieve/pii/S1097276500801537|journal=Molecular Cell|language=en|volume=2|issue=5|pages=539–548|doi=10.1016/S1097-2765(00)80153-7}}</ref> The binding of SNAP to the lateral side of [[SNARE (protein)|SNARE]] complex rod takes place at the membrane during the priming step. This interaction requires intact N-terminal residues 63 and 37 on the [[SNARE (protein)|SNARE]] protein <ref name=":3" /> which may directly interact with one or more alpha-helical domains of the SNAP. NSF binding to [[NAPA (gene)|α-SNAP]] has also been shown to be negatively impacted by the phosphorylation of NSF or the Y83E mutant that displays phosphomimic properties.<ref>{{Cite journal|last=Morgan|first=Alan|last2=Burgoyne|first2=Robert D.|date=2004-11|title=Membrane Traffic: Controlling Membrane Fusion by Modifying NSF|url=https://linkinghub.elsevier.com/retrieve/pii/S0960982204008504|journal=Current Biology|language=en|volume=14|issue=22|pages=R968–R970|doi=10.1016/j.cub.2004.10.045}}</ref> The unwinding of the coiled-coil structures following ATP hydrolysis by NSF is also accompanied by a conformational change in syntaxin (SNARE) prior to vesicle fusion.

These structural finding have been confirmed by use of [[Electron microscope|Quick-Freeze/Deep-Etch EM]] that also describes the ternary [[SNARE (protein)|SNARE]] complex as a similarly elongated rod-like assembly around the [[SNARE (protein)|SNARE]] proteins with N-terminal binding of SNAP.<ref>{{Cite journal|last=Hanson|first=Phyllis I|last2=Roth|first2=Robyn|last3=Morisaki|first3=Hiroshi|last4=Jahn|first4=Reinhard|last5=Heuser|first5=John E|date=1997-08|title=Structure and Conformational Changes in NSF and Its Membrane Receptor Complexes Visualized by Quick-Freeze/Deep-Etch Electron Microscopy|url=https://linkinghub.elsevier.com/retrieve/pii/S0092867400805127|journal=Cell|language=en|volume=90|issue=3|pages=523–535|doi=10.1016/S0092-8674(00)80512-7}}</ref>

The [[Saccharomyces cerevisiae|yeast homolog]] Sec17, pictured above contains fourteen [[Alpha helix|α-helices]] and has the approximate dimensions of 85 [[Angstrom|Å]] × 35 Å × 35 Å with multiple conserved residues along the packing face of the protein.<ref name=":2" /> Blocking of Sec17/SNAP interaction with SNAREs and Sec18/NSF has recently been reported in the literature using small molecules binding to [[Phosphatidic acid|PA (phosphatidic acid)]] to prevent priming activity and limit vesicle fusion.<ref name=":5" />
== Role in Disease ==
Blocking of SNARE complex assembly, and therefore indirectly interfering with SNAP function, has a wide variety of application as evidenced by the diverse treatment utility of Botox which can be used to block vesicle fusion and neurotransmitter release. Targeting of SNAP protein receptors has been found both to be disease causing and has broad application when targeted with therapeutics.

Outlined below are recent publications indicating more direct associations of SNAPs in disease course and development. Notably, the role of SNAPs in disease states is still primarily related to its interaction as part of the [[SNARE (protein)|SNARE]] complexes. Abnormal levels of multiple [[Membrane vesicle trafficking|vesicular trafficking]] proteins are often observed in conjunction and a compound effect may lead to a disruption in signaling.

=== Colorectal Cancer ===
In a studies of [[colorectal cancer]] of [[Neuroendocrine tumor|neuroendocrine markers,]] the expression of [[NAPA (gene)|α-SNAP]] and [[NAPB|β-SNAP]] were found to be higher in undifferentiated cells when compared to controls, and were associated with more aggressive disease.<ref>{{Cite journal|last=Grabowski|first=Patricia|last2=Schönfelder|first2=Julia|last3=Ahnert-Hilger|first3=Gudrun|last4=Foss|first4=Hans-Dieter|last5=Heine|first5=Bernhard|last6=Schindler|first6=Isabell|last7=Stein|first7=Harald|last8=Berger|first8=Gerd|last9=Zeitz|first9=Martin|last10=Scherübl|first10=Hans|date=2002-09|title=Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum|url=http://link.springer.com/10.1007/s00428-002-0650-9|journal=Virchows Archiv|language=en|volume=441|issue=3|pages=256–263|doi=10.1007/s00428-002-0650-9|issn=0945-6317}}</ref> Similarly, expression of other vesicle trafficking proteins including [[synaptophysin]], [[SNAP25|SNAP-25 (SNARE)]], [[VAMP2]] and [[Syntaxin|syntaxin-1]] were also found to have various levels of increase [[Small-cell carcinoma|small cell undifferentiated carcinomas]].<ref name=":8" />

Aberrant of signaling and trafficking of proteins in cancer cells has been previously reported based on SNARE complex interactions for [[NAPA (gene)|α-SNAP]] within implication of it's role as a negative regulator of autophagy and the MAPK pathway thorough dephosphorylating.<ref name=":13">{{Cite journal|last=Meng|first=Jianghui|last2=Wang|first2=Jiafu|date=2015-08|title=Role of SNARE proteins in tumourigenesis and their potential as targets for novel anti-cancer therapeutics|url=https://linkinghub.elsevier.com/retrieve/pii/S0304419X15000347|journal=Biochimica et Biophysica Acta (BBA) - Reviews on Cancer|language=en|volume=1856|issue=1|pages=1–12|doi=10.1016/j.bbcan.2015.04.002}}</ref> Depletion of [[NAPA (gene)|α-SNAP]] has been reported to impair Golgi body integrity and assembly of vesicle fusion proteins at signaling junctions, while overexpression delays apoptosis in HeLa cells.<ref name=":13" />

=== Epilepsy ===
Association of [[NAPA (gene)|α-SNAP]] with [[SNARE (protein)|v-SNARE (vesicle)]], t-SNARE (target) proteins with [[Syntaxin|synatxin-1]] forms the 7S [[SNARE (protein)|SNARE]] complex in [[Neuron|central neurons]] used in vesicle transport.<ref name=":7" /> Downregulation of alpha SNAPs has been documented to increase susceptibility to [[Seizure|seizures]] in rodent models. In the same study a decrease alpha SNAP expression has been observed in patients with [[temporal lobe epilepsy]] as well as in the epileptic [[rat model]]. <ref>{{Cite journal|last=Xi|first=Zhiqin|last2=Deng|first2=Wanni|last3=Wang|first3=Liang|last4=Xiao|first4=Fei|last5=Li|first5=Jie|last6=Wang|first6=Zhihua|last7=Wang|first7=Xin|last8=Mi|first8=Xiujuan|last9=Wang|first9=Na|last10=Wang|first10=Xuefeng|date=2015-11|title=Association of Alpha-Soluble NSF Attachment Protein with Epileptic Seizure|url=http://link.springer.com/10.1007/s12031-015-0596-4|journal=Journal of Molecular Neuroscience|language=en|volume=57|issue=3|pages=417–425|doi=10.1007/s12031-015-0596-4|issn=0895-8696}}</ref> An accumulation of the 7S complexes was also observed in synapse of the [[hippocampus]] in chronic rodent models for [[epilepsy]].<ref>{{Cite journal|last=Matveeva|first=Elena A.|last2=Vanaman|first2=Thomas C.|last3=Whiteheart|first3=Sidney W.|last4=Slevin|first4=John T.|date=2007-03|title=Asymmetric accumulation of hippocampal 7S SNARE complexes occurs regardless of kindling paradigm|url=https://linkinghub.elsevier.com/retrieve/pii/S092012110600430X|journal=Epilepsy Research|language=en|volume=73|issue=3|pages=266–274|doi=10.1016/j.eplepsyres.2006.11.003|pmc=PMC1868484|pmid=17174072}}</ref> The suspected mechanism may involve priming of the SNARE-SNAP-NSF complex to increase vesicle fusion at the membranes, however the exact mechanism by which the upregulation of the 7S complex occurs in not well understood.

=== Down Syndrome ===
In a study of fetal brain development [[NAPB|β-SNAP]] levels were found to be comparable between samples taken from [[Down syndrome|Down syndrome (DS)]] affected and non-affected individuals. Presence of [[NAPA (gene)|α-SNAP]] in comparison was only observed in half of [[Down syndrome|DS]] affected samples.<ref>{{Citation|last=Weitzdoerfer|first=R.|title=Fetal life in Down Syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure|date=2001|url=http://link.springer.com/10.1007/978-3-7091-6262-0_5|work=Protein Expression in Down Syndrome Brain|pages=59–70|editor-last=Lubec|editor-first=Gert|place=Vienna|publisher=Springer Vienna|language=en|doi=10.1007/978-3-7091-6262-0_5|isbn=978-3-211-83704-7|access-date=2021-11-08|last2=Dierssen|first2=M.|last3=Fountoulakis|first3=M.|last4=Lubec|first4=G.}}</ref><ref name=":6" /> Reduction in [[NAPA (gene)|α-SNAP]] along with other observed changes to protein expression may indicate impaired [[synaptogenesis]] from very early on in development.

=== Huntington's Disease ===
Vesicle fusion proteins evaluated in a study of rodent [[Huntington's disease|Huntington's disease (HD)]] model found higher levels of [[NAPA (gene)|α-SNAP]] in the [[hippocampus]] and lower expression in the [[striatum]] of [[Huntington's disease|HD]] mice compared to controls.<ref>{{Cite journal|last=Morton|first=A.J.|last2=Faull|first2=R.L.M.|last3=Edwardson|first3=J.M.|date=2001-09|title=Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease|url=https://linkinghub.elsevier.com/retrieve/pii/S0361923001006116|journal=Brain Research Bulletin|language=en|volume=56|issue=2|pages=111–117|doi=10.1016/S0361-9230(01)00611-6}}</ref> It is notable that multiple other proteins involved in vesicle fusion also experienced decreased expression in the striatum along with increased expression in the hippocampus and the contributing effects could not yet be deconvoluted. The interaction of mutant [[Huntingtin|''huntingtin'' gene]] and vesicle fusion proteins may also be potentially responsible for deranged synaptic development or degeneration observed in the condition.<ref name=":6" />

=== Prion Disease ===
Upregulation of [[NAPA (gene)|α-SNAP]] was observed in mice with knock out 14-3-3 gamma protein suggesting a relationship between progression but not the pathogenesis of [[Creutzfeldt–Jakob disease|Creutzfeldt-Jakob Disease (CJD)]]. Increased levels of [[14-3-3 protein]]<nowiki/>s are used diagnostically to confirm [[Creutzfeldt–Jakob disease|CJD]] but based on literature may not play a causal role in the disease.<ref>{{Cite journal|last=Steinacker|first=Petra|last2=Schwarz|first2=Petra|last3=Reim|first3=Kerstin|last4=Brechlin|first4=Peter|last5=Jahn|first5=Olaf|last6=Kratzin|first6=Hartmut|last7=Aitken|first7=Alastair|last8=Wiltfang|first8=Jens|last9=Aguzzi|first9=Adriano|last10=Bahn|first10=Erik|last11=Baxter|first11=Helen C.|date=2005-02-15|title=Unchanged Survival Rates of 14-3-3γ Knockout Mice after Inoculation with Pathological Prion Protein|url=https://journals.asm.org/doi/10.1128/MCB.25.4.1339-1346.2005|journal=Molecular and Cellular Biology|language=en|volume=25|issue=4|pages=1339–1346|doi=10.1128/MCB.25.4.1339-1346.2005|issn=0270-7306|pmc=PMC547999|pmid=15684385}}</ref><ref name=":6" />

== Intervention Strategies ==
Interaction of [[NAPA (gene)|α-SNAP]] with [[AMPA receptor|AMPA receptors]] for glutamate may be potential target to improve [[synaptic plasticity]] through mechanism of stabilization at membranes where SNAPs are present. <ref name=":6" /> Additionally, [[NAPA (gene)|α-SNAP]] has been implicated in surfactant and acrosomal exocytosis in alveolar cells and sperm cells respectively, although the exact mechanism are yet to be identified. SNAP protein isoforms are not a currently druggable target and may prove difficult to target as they serve primarily a scaffolding role. Insufficiency in expression is indicated in a number of neurodegenerative and immune related conditions where the primary treatment strategy may focus on gene-therapy as replacement option.

The potential for application to clinical therapy include the development of targeted regulators for [[NAPB|β-SNAP]] for treatment of CNS pathologies including epilepsy.<ref name=":0" /> Use of [[Inositol-polyphosphate 5-phosphatase|Inositol Polyphosphates]] to inhibit [[NAPB|β-SNAP]] and [[Synaptotagmin|synaptogamin]] interactions can also block neurotransmitter release and may be potentially useful in broader regulations of synaptic networks.

Small molecule agents that can be used to block [[SNARE (protein)|SNARE]] complex activity through interaction with SNAPs and have been utilized [[In vitro|''in vitro'']] <ref name=":5" /> but their practical use may extend to in vivo systems as well. In colorectal cancers where elevated [[NAPA (gene)|α-SNAP]] levels were observed, siRNA technology may be employed to deplete overexpression,<ref name=":6" /> but the novelty of this technology may be limited until further experience with the platform is gather and safety is well-demonstrated.
== References ==

[[Category:Wikipedia Student Program]]

<references responsive="0" />

Revision as of 14:25, 15 December 2021

Soluble N-ethylmaleimide-Sensitive Factor Attachment Proteins (SNAP, or Sec17p in yeast) are a family of cytosolic adaptor proteins involved in vesicular fusion at membranes during intracellular transport and exocytosis. SNAPs interact with proteins of the SNARE complex and NSF to play a key role in recycling the components of the fusion complex. SNAPs are involved in the priming of the vesicle fusion complex during assembly, as well as in the disassembly following a vesicle fusion event. Following membrane fusion, the tethering SNARE proteins complex disassembles in response to steric changes originating from the ATPase NSF. The energy provided by NSF is transferred throughout the SNARE complex and SNAP, allowing the proteins to untangle, and recycled for future fusion events. Mammals have three SNAP genes: α-SNAP, β-SNAP, and γ-SNAP. α- and γ-SNAP are expressed throughout the body, while β-SNAP is specific to the brain. Yeast homologs of the human SNAP is known as Sec17 (pictured in the infobox).

Soluble NSF Attachment Protein
Sec17 is yeast is an ortholog of the human SNAP and acts in membrane fusion of vesicles. SNAP complexes with SNARE and NSF to form 20S particles.
Identifiers
SymbolSNAP
PfamPF14938
PROSITEPDOC50892 PDOC50192, PDOC50892
CDDcd15832
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Function

The function of SNAP proteins have been primarily related to the role which the play in the assemble and disassembly of SNARE complex required for vesicle fusion events. According to the SNARE hypothesis developed in the early 1990s, SNAP protein are localized to the membranes and are central in mediating Ca2+ dependent vesicle fusion at these these sites. SNAPs associate with the proteins of the SNARE (SNAP REceptor) complex, a class of type II integral membrane protein, as well as the ATPase NSF, largely based on electrostatic interactions.[1][2] The interaction of the SNAPs with SNAREs takes place before interaction of the complex with NSF (Sec18 in yeast) suggesting a sequence for the priming assembly may be necessary.[1] [3] The assembled complex which includes SNAP, SNARE, and NSF is known as the 20S complex. Some of the first proteins identified as the receptors of SNAPs were syntaxin 1, SNAP-25 (synaptosome associated protein, 25kDa), and VAMP (synaptobrevin).[4] These proteins are contain transmembrane regions can can be found in both intracellular vesicles and as part of extracellular trafficking machinery. Figure 1 shows interactions of the vesicular and membrane SNARE proteins with NSF and SNAP in the assembly, fusion, and disassembly process that accompanies vesicle fusion events.

Initial binding of NSF to SNAP been is likely related to interactions of the 63 N-terminal and 37 C-terminal amino acid residues of SNAP with NSF protein.[5] The interaction with SNAP stimulates the ATPase activity of the NSF when assembled into the 20S complex, and ultimately leads to ATP hydrolysis that result in the disruption of the heterooligomeric complex.[6] This has the potential to reduce or block synaptic transmission, ultimately leading to the loss of signaling downstream. Further information on this is included in the toxicology section below.

While assembly of the complex can take place under only conditions where a components and a membrane is present, disassembly requires that NSF can hydrolyze ATP.[1] Use of chelating agents, non-hydrolysable analogues of GTP, or application of an alkylating agent N-ethylmaleimide (NEM), therefore, has been used to demonstrate prevention of vesicle fusion in vitro.[4] Blocking the assembly of the 20S complex also prevents the ATP-hydrolysis reaction from taking place at NSF.

Limitations of the Original SNARE Theory of Vesicle Fusion

Fig 1. The vesicle fusion complex. The vesicle approaches the membrane and proteins including SNAP, NSF, synaptobrevin, syntaxin, and synaptotagmin SNARE proteins form the 20S SNARE Complex required for fusion. The ATPase action of NSF drives disassembly post priming of the complex. Ca2+ influx due to depolarization drives vesicle fusion to the membrane and release of neurotransmitters.

It is important to note, however, that the SNARE Theory of the vesicle fusion, which encompasses the action description of SNAREs, SNAP, and NSF, does not completely explain all known vesicle fusion events.[1] The theory was formulated by James Rothman and co-workers staring in the early 1990s and originally predicted that SNAPs and NSF recognized paired vesicle-SNARE (v-SNARE)/ target-SNARE (t-SNARE) complexes at membranes and bound to them thus creating the 20S complex.[4][7]

All mechanistic considerations of vesicle fusion by SNARE complexes is not fully explained by this earlier version of the theory. Specifically, for data generated experimentally in recent years lead some to question the completeness of the model. Although it was known since the 1960s that Ca2+ influx was responsible for synaptic signaling, a collaboration in 1992 between Thomas Südhof and Reinhardt Jahn tied the link between calcium, SNARE complexes and synaptic signaling. At the time, outdated considerations could not account for the rapid release of neurotransmitters into synaptic clefts, as the turnaround was thought to be limited by the rate of recycling of the SNAREs. Consensus, however, has been maintained around the participating proteins (SNAPs, NSF, SNAREs) and their function as part of membrane fusion systems across the the cell, in both synaptic and vacuolar systems including the Golgi transport .[4]

Significance in CNS Signaling

Further studies demonstrated that the ATP hydrolysis step occurs prior to a calcium ion mediated fusion event, and thus, that SNAP and NSF proteins initiate disassembly the 20S complex before the docking event takes place directly at the membrane. Once intracellular Ca2+ achieve significantly high levels to facilitate docking, the molecular clamp protein called synaptotagmin acts in a Ca2+ sensitive manner to facilitate fusion of the vesicle to the membrane.[8][4] The exocytosis of neurotransmitters as regulated by Ca2+ is faster kinetically than would be possible by the SNARE-recycling model alone.[6][4] Figure 1 summarizes the updated model of the SNARE hypothesis.

The existence of primed vesicles ready for fusion at the pre-synaptic membrane due to interactions of SNAP and NSF preceding vesicle fusion more closely predicts the mechanism of neurotransmitter release as it does not see the delay predicted by the traditional SNARE mechanism for recycling. A depolarizing current of the pre-synaptic neuron leads to the opening of voltage dependent ion channels that permit the influx of Ca2+ into the cell, and then initiate the fusion of vesicles at a rate of one vesicle per 100us. [4]

Significance in Toxicology

Action of botulinum toxin at the synaptic nerve terminals interferes with the assembly of the 20S SNARE complex and prevents the signaling.

The 20S complex is a known to be target for Clostridium neurotoxins including Botulinum A, C. and E, which block synaptic transmission by disrupting the complex and preventing neurotransmitter release into the synaptic space.[9] The disruption to synaptic transmission is the result of the serotype B toxins cleaving only VAMP-2/synaptobrevin-2 but not type 1 SNARE proteins. These toxins do not directly interact with SNAP but the resultant is the failure to form the 20S vesicle fusion complex.[4][8] Botulinum toxin impairs synaptic transmission is impaired at the neuromuscular junction due to blocking of acetyl choline release onto the endplate leading to muscle paralysis and, if left untreated, death.[10] Poisoning by botulinum toxin generally occurs through ingestion of material contaminated with the toxin producing bacteria or absorbance of the toxin through the skin.

SNARE complexes containing SNAP are also targets for tetanus toxin which likewise inhibit vesicle fusion and neurotransmitter release through anterograde transport of the toxin into the CNS.[1][11][10] Prevention of 20S snare complex assembly due to cleaved components prevents SNAPs from interaction with the receptor proteins in a non-competitive manner.

Genetics

Expression of the three SNAP proteins in mammalian is tissue dependent with α-SNAP (33kD) and γ-SNAP (36kD) expressed throughout the body, and β-SNAP (34kD) primarily found in brain tissues.[1] α-SNAP and β-SNAP share approximately 83% sequence homology and are encoded by NAPA and NAPB on chromosomes 19 and 18, respectively in humans.[12] β-SNAP protein is encoded by the NAPB on chromosome 20. Changes in temporal expression have been observed in rodent models during embryonic development but similar changes in humans is yet to be verified. [1] Expression data in the early years after discovery of the protein group in the 1990s were primarily confirmed though use of Western blot and allowed expression of the mRNA and later cDNA. Use of Immunofluorescent localization showed strong association of the proteins to intracellular membranes including the ER and Golgi bodies as well as vesicles. [13]

Deletions in α-SNAP gene have also been found to be lethal in utero in rodent models with hyh (hydrocephalus with hop gait) [14] while hyh due to missense mutations lead to 40% lower levels of expression.[15] The effects of the mutations develop in utero and become more sever over time, ultimately leading to worsening hydrocephalus and death. Reduced expression of α-SNAP in hyh/hyh mice is also associated with CD4 T-cell effector cytokine deficiency. [16]

Yeast (S. cerevisiae) homolog of the SNAP gene known as Sec17p has 67% similarity to mammalian α-SNAP [1] or approximately 34% homology with alpha and 33% with beta.[13] It has been studied based on its function in yeast vacuolar fusion.[2] The lethality of the double null mutation in this animal highlights the importance of this class of proteins in intra and inter-cell communication and survival.

Structure

Use of TEM and FRET imaging techniques was widely applied at the beginning of the century to resolve the SNARE complex and expanded to include SNAP proteins as well. The 20S complex ultimately forms a rod of 2.5nm width by 15nm in length that assembles along the axis of two coiled coils of interacting SNARE proteins.[4][17] The binding of SNAP to the lateral side of SNARE complex rod takes place at the membrane during the priming step. This interaction requires intact N-terminal residues 63 and 37 on the SNARE protein [17] which may directly interact with one or more alpha-helical domains of the SNAP. NSF binding to α-SNAP has also been shown to be negatively impacted by the phosphorylation of NSF or the Y83E mutant that displays phosphomimic properties.[18] The unwinding of the coiled-coil structures following ATP hydrolysis by NSF is also accompanied by a conformational change in syntaxin (SNARE) prior to vesicle fusion.

These structural finding have been confirmed by use of Quick-Freeze/Deep-Etch EM that also describes the ternary SNARE complex as a similarly elongated rod-like assembly around the SNARE proteins with N-terminal binding of SNAP.[19]

The yeast homolog Sec17, pictured above contains fourteen α-helices and has the approximate dimensions of 85 Å × 35 Å × 35 Å with multiple conserved residues along the packing face of the protein.[5] Blocking of Sec17/SNAP interaction with SNAREs and Sec18/NSF has recently been reported in the literature using small molecules binding to PA (phosphatidic acid) to prevent priming activity and limit vesicle fusion.[3]

Role in Disease

Blocking of SNARE complex assembly, and therefore indirectly interfering with SNAP function, has a wide variety of application as evidenced by the diverse treatment utility of Botox which can be used to block vesicle fusion and neurotransmitter release. Targeting of SNAP protein receptors has been found both to be disease causing and has broad application when targeted with therapeutics.

Outlined below are recent publications indicating more direct associations of SNAPs in disease course and development. Notably, the role of SNAPs in disease states is still primarily related to its interaction as part of the SNARE complexes. Abnormal levels of multiple vesicular trafficking proteins are often observed in conjunction and a compound effect may lead to a disruption in signaling.

Colorectal Cancer

In a studies of colorectal cancer of neuroendocrine markers, the expression of α-SNAP and β-SNAP were found to be higher in undifferentiated cells when compared to controls, and were associated with more aggressive disease.[20] Similarly, expression of other vesicle trafficking proteins including synaptophysin, SNAP-25 (SNARE), VAMP2 and syntaxin-1 were also found to have various levels of increase small cell undifferentiated carcinomas.[16]

Aberrant of signaling and trafficking of proteins in cancer cells has been previously reported based on SNARE complex interactions for α-SNAP within implication of it's role as a negative regulator of autophagy and the MAPK pathway thorough dephosphorylating.[21] Depletion of α-SNAP has been reported to impair Golgi body integrity and assembly of vesicle fusion proteins at signaling junctions, while overexpression delays apoptosis in HeLa cells.[21]

Epilepsy

Association of α-SNAP with v-SNARE (vesicle), t-SNARE (target) proteins with synatxin-1 forms the 7S SNARE complex in central neurons used in vesicle transport.[15] Downregulation of alpha SNAPs has been documented to increase susceptibility to seizures in rodent models. In the same study a decrease alpha SNAP expression has been observed in patients with temporal lobe epilepsy as well as in the epileptic rat model. [22] An accumulation of the 7S complexes was also observed in synapse of the hippocampus in chronic rodent models for epilepsy.[23] The suspected mechanism may involve priming of the SNARE-SNAP-NSF complex to increase vesicle fusion at the membranes, however the exact mechanism by which the upregulation of the 7S complex occurs in not well understood.

Down Syndrome

In a study of fetal brain development β-SNAP levels were found to be comparable between samples taken from Down syndrome (DS) affected and non-affected individuals. Presence of α-SNAP in comparison was only observed in half of DS affected samples.[24][12] Reduction in α-SNAP along with other observed changes to protein expression may indicate impaired synaptogenesis from very early on in development.

Huntington's Disease

Vesicle fusion proteins evaluated in a study of rodent Huntington's disease (HD) model found higher levels of α-SNAP in the hippocampus and lower expression in the striatum of HD mice compared to controls.[25] It is notable that multiple other proteins involved in vesicle fusion also experienced decreased expression in the striatum along with increased expression in the hippocampus and the contributing effects could not yet be deconvoluted. The interaction of mutant huntingtin gene and vesicle fusion proteins may also be potentially responsible for deranged synaptic development or degeneration observed in the condition.[12]

Prion Disease

Upregulation of α-SNAP was observed in mice with knock out 14-3-3 gamma protein suggesting a relationship between progression but not the pathogenesis of Creutzfeldt-Jakob Disease (CJD). Increased levels of 14-3-3 proteins are used diagnostically to confirm CJD but based on literature may not play a causal role in the disease.[26][12]

Intervention Strategies

Interaction of α-SNAP with AMPA receptors for glutamate may be potential target to improve synaptic plasticity through mechanism of stabilization at membranes where SNAPs are present. [12] Additionally, α-SNAP has been implicated in surfactant and acrosomal exocytosis in alveolar cells and sperm cells respectively, although the exact mechanism are yet to be identified. SNAP protein isoforms are not a currently druggable target and may prove difficult to target as they serve primarily a scaffolding role. Insufficiency in expression is indicated in a number of neurodegenerative and immune related conditions where the primary treatment strategy may focus on gene-therapy as replacement option.

The potential for application to clinical therapy include the development of targeted regulators for β-SNAP for treatment of CNS pathologies including epilepsy.[1] Use of Inositol Polyphosphates to inhibit β-SNAP and synaptogamin interactions can also block neurotransmitter release and may be potentially useful in broader regulations of synaptic networks.

Small molecule agents that can be used to block SNARE complex activity through interaction with SNAPs and have been utilized in vitro [3] but their practical use may extend to in vivo systems as well. In colorectal cancers where elevated α-SNAP levels were observed, siRNA technology may be employed to deplete overexpression,[12] but the novelty of this technology may be limited until further experience with the platform is gather and safety is well-demonstrated.

References

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  13. ^ a b Whiteheart, Sidney W.; Griff, Irene C.; Brunner, Michael; Clary, Douglas O.; Mayer, Thomas; Buhrow, Susan A.; Rothman, James E. (1993-03). "SNAP family of NSF attachment proteins includes a brain-specific isoform". Nature. 362 (6418): 353–355. doi:10.1038/362353a0. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)
  14. ^ Chae, Teresa H; Kim, Seonhee; Marz, Karla E; Hanson, Phyllis I; Walsh, Christopher A (2004-02-01). "The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate". Nature Genetics. 36 (3): 264–270. doi:10.1038/ng1302. ISSN 1061-4036.
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  16. ^ a b Miao, Yong; Bhushan, Jaya; Dani, Adish; Vig, Monika (2017-05-11). "Na+ influx via Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation". eLife. 6: e25155. doi:10.7554/eLife.25155. ISSN 2050-084X. PMC 5459575. PMID 28492364.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
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  18. ^ Morgan, Alan; Burgoyne, Robert D. (2004-11). "Membrane Traffic: Controlling Membrane Fusion by Modifying NSF". Current Biology. 14 (22): R968–R970. doi:10.1016/j.cub.2004.10.045. {{cite journal}}: Check date values in: |date= (help)
  19. ^ Hanson, Phyllis I; Roth, Robyn; Morisaki, Hiroshi; Jahn, Reinhard; Heuser, John E (1997-08). "Structure and Conformational Changes in NSF and Its Membrane Receptor Complexes Visualized by Quick-Freeze/Deep-Etch Electron Microscopy". Cell. 90 (3): 523–535. doi:10.1016/S0092-8674(00)80512-7. {{cite journal}}: Check date values in: |date= (help)
  20. ^ Grabowski, Patricia; Schönfelder, Julia; Ahnert-Hilger, Gudrun; Foss, Hans-Dieter; Heine, Bernhard; Schindler, Isabell; Stein, Harald; Berger, Gerd; Zeitz, Martin; Scherübl, Hans (2002-09). "Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum". Virchows Archiv. 441 (3): 256–263. doi:10.1007/s00428-002-0650-9. ISSN 0945-6317. {{cite journal}}: Check date values in: |date= (help)
  21. ^ a b Meng, Jianghui; Wang, Jiafu (2015-08). "Role of SNARE proteins in tumourigenesis and their potential as targets for novel anti-cancer therapeutics". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1856 (1): 1–12. doi:10.1016/j.bbcan.2015.04.002. {{cite journal}}: Check date values in: |date= (help)
  22. ^ Xi, Zhiqin; Deng, Wanni; Wang, Liang; Xiao, Fei; Li, Jie; Wang, Zhihua; Wang, Xin; Mi, Xiujuan; Wang, Na; Wang, Xuefeng (2015-11). "Association of Alpha-Soluble NSF Attachment Protein with Epileptic Seizure". Journal of Molecular Neuroscience. 57 (3): 417–425. doi:10.1007/s12031-015-0596-4. ISSN 0895-8696. {{cite journal}}: Check date values in: |date= (help)
  23. ^ Matveeva, Elena A.; Vanaman, Thomas C.; Whiteheart, Sidney W.; Slevin, John T. (2007-03). "Asymmetric accumulation of hippocampal 7S SNARE complexes occurs regardless of kindling paradigm". Epilepsy Research. 73 (3): 266–274. doi:10.1016/j.eplepsyres.2006.11.003. PMC 1868484. PMID 17174072. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  24. ^ Weitzdoerfer, R.; Dierssen, M.; Fountoulakis, M.; Lubec, G. (2001), Lubec, Gert (ed.), "Fetal life in Down Syndrome starts with normal neuronal density but impaired dendritic spines and synaptosomal structure", Protein Expression in Down Syndrome Brain, Vienna: Springer Vienna, pp. 59–70, doi:10.1007/978-3-7091-6262-0_5, ISBN 978-3-211-83704-7, retrieved 2021-11-08
  25. ^ Morton, A.J.; Faull, R.L.M.; Edwardson, J.M. (2001-09). "Abnormalities in the synaptic vesicle fusion machinery in Huntington's disease". Brain Research Bulletin. 56 (2): 111–117. doi:10.1016/S0361-9230(01)00611-6. {{cite journal}}: Check date values in: |date= (help)
  26. ^ Steinacker, Petra; Schwarz, Petra; Reim, Kerstin; Brechlin, Peter; Jahn, Olaf; Kratzin, Hartmut; Aitken, Alastair; Wiltfang, Jens; Aguzzi, Adriano; Bahn, Erik; Baxter, Helen C. (2005-02-15). "Unchanged Survival Rates of 14-3-3γ Knockout Mice after Inoculation with Pathological Prion Protein". Molecular and Cellular Biology. 25 (4): 1339–1346. doi:10.1128/MCB.25.4.1339-1346.2005. ISSN 0270-7306. PMC 547999. PMID 15684385.{{cite journal}}: CS1 maint: PMC format (link)
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