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MAP6

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This article is about the protein. For the South Korean band, see MAP6 (band).
MAP6
Identifiers
AliasesMAP6, MTAP6, N-STOP, STOP, MAP6-N, microtubule associated protein 6
External IDsOMIM: 601783; MGI: 1201690; HomoloGene: 7850; GeneCards: MAP6; OMA:MAP6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4135

17760

Ensembl

ENSG00000171533

ENSMUSG00000055407

UniProt

Q96JE9

Q7TSJ2

RefSeq (mRNA)

NM_033063
NM_207577

NM_001043355
NM_001048167
NM_010837

RefSeq (protein)

NP_149052
NP_997460

NP_001036820
NP_001041632
NP_034967

Location (UCSC)Chr 11: 75.59 – 75.67 MbChr 7: 98.92 – 98.99 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Microtubule-associated protein 6 (MAP6) or stable tubule-only polypeptide (STOP or STOP protein) is a protein that in humans is encoded by the MAP6 gene.[5][6]

This gene encodes a microtubule-associated protein (MAP). The encoded protein is a calmodulin binding, and calmodulin-regulated protein that is involved in microtubule stabilization.

MAP6 localization is present throughout neuronal maturation and axonal development.[7] It protects microtubules under drug and cold induced depolymerization by reducing the shrinking rate and promoting rescue events. A deficit in MAP6 protein levels is characterized by behavioral impairments, most notably schizophrenia.

Structure

A murine isoform of MAP6, MAP6-N, has 3 major domains:

12 calmodulin binding domains, 3 Mn domains, and 3-6 Mc domains.[8]

  • Calmodulin-binding domains: 12 of the calmodulin-binding domains exist in MAP6-N. In vitro studies show that Ca+2-Calmodulin (CaM) binding to MAP6 prevents binding to microtubules. According to a model proposed by Ramkumar and collaborators,[8] upon synaptic activity, the Ca+2-CaM complex forms, where it detaches MAP6 from adjacent microtubules, and activates Ca+2/calmodulin-dependent protein kinase II (CaMKII). When Ca+2 level decreases, CaM is released from MAP6 and is then phosphorylated by CaMKII.The phosphorylated MAP6 cannot re-associate with microtubules. Instead, the phosphorylated MAP6 binds and stabilizes synaptic F-actin. The large number of calmodulin-binding domains overlapping the Mn and Mc modules in MAP6 provides evidence that MAP6 binding to microtubules is likely to be tightly regulated in cells.
  • Mn domains: 3 of these exist in MAP6-N. They partially overlap the calmodulin binding domain and stabilize microtubules against both cold and nocodazole-induced depolymerization by forming bridges with adjacent tubulin heterodimers either between protofilaments, or longitudinally within the same protofilament.[8]
  • Mc domains: The Mc domains are central repeat domains that each encompass a calmodulin binding region. Mc regions are only in present in vertebrates and are thus absent from fish, frogs, lizards or birds.[8] In vitro studies show Mc modules act as cold sensors, where cold temperature induces a conformational change in Mc modules that subsequently allow them to interact with microtubules.

MAP6 can also associate with the Golgi apparatus through palmitoylation of their N-terminal domains.[9] N-terminal cysteines of MAP6 domain-containing protein 1 (MAP6d1), a postnatally expressed isoform in the mouse central nervous system, are palmitoylated by DHHC-type palmitoylating enzymes. Through palmitoylation, MAP6 can be targeted to a newly formed axon and is involved in microtubule and membrane shuttling.

Function and Regulation

MAP6 is a multi-functional protein. While it is involved with microtubules, it can also be involved in neuroreceptor homeostasis, endocytosis, nuclear function, and signal transduction pathways.

MAP6 interacts with microtubules by localizing in the lumen of microtubules. MAP6 alters the conformation of a growing microtubules by inducing the microtubule to coil into a left-handed helix with a long-range helicity with a pitch of 5.5 ± 0.8 μm.[10] This coiling pattern requires the Mn and Mc modules, as well as the first 35 N-terminal residues. MAP6 is also shown to be involved at the tip of the microtubule. Additionally, during microtubule polymerization, MAP6 induces the formation of stable apertures in the lattice, which is likely used to relieve mechanical stress.

In neuroreceptor homeostasis, MAP6 was consistently identified in synaptic proteomes, even though microtubules are only transiently present in both pre- and post-synaptic compartments of axonal boutons or dendritic spines. This suggests that MAP6 has microtubule independent roles as well. MAP6 is also associated with subicular neurons from the hippocampus, where it is involved with the receptors Neuropilin1, Plexin D1, and VEGFR2—which together make up the tripartite Semaphorin 3E receptor, which aids in the formation of the fornix. A knockout of the MAP6 gene in mice led to the absence of the post-commissural part of the fornix, producing a disconnect between the hippocampus and the hypothalamus.[11]

MAP6 is also involved in the olfactory bulb and the hippocampus, two regions where adult neurogenesis is known to occur. In neurogenesis studies with mice with the MAP6 knockout, there was an increase in the number of proliferating cells in the olfactory epithelium with increased apoptosis,[12] while there was a decrease in proliferating cells in the hippocampus.[13] The exact mechanism behind how MAP6 aids in neurogenesis is unclear.

A MAP6-related protein, TbSAXO, has been discovered in Trypanosoma brucei.[14] The domains of the protein responsible for microtubule binding and stabilizing share homologies with the Mn domains of MAP6.TbSAXO is an axonemal protein that plays a role in flagellum motility, showing that a MAP6-related protein can play a role in flagellum motility as well.

Psychiatric disorders

MAP6 functions as a neuronal protein that aids in microtubule stabilization. Studies with mice that have knockouts of MAP6 (MAP6 KO mice) are viable, but they show biological and behavioral alterations, which are similar to symptoms of schizophrenia.

Schizophrenia

MAP6 KO mice show hyperactivity, fragmentation of normal activity, anxiety-like behavior, social withdrawal, and impaired maternal behavior leading to the death of pups.[5] These symptoms correspond to changes in synaptic plasticity, which lead to large alterations in synaptic responses.The symptoms of the MAP6 KO mice are mainly treated by antipsychotic drugs or Epothilone D (Epo D), a microtubule-stabilizing molecule, which has also been shown to alleviate the synaptic plasticity defects in MAP6 KO mice.[15] Therefore, MAP6 KO mice serve as useful models for the treatment and pathophysiology of schizophrenia. In addition to schizophrenia, MAP6 KO mice also display a reduced volume of the cerebellum and the thalamus. Moreover, the mice had other brain anomalies, characterized by an altered size, integrity and spatial orientation of some neuronal tracks such as the anterior commissure, the mammillary tract, the corpus callosum, the corticospinal tract, the fasciculus retroflexus and the fornix.[16]

Autism

In a study conducted with the plasmas of children displaying classic-onset autism, the concentration of MAP6 protein levels were lower than that of healthy children.[17] In MAP6 KO mice conducted in the same study, there was a reduction in pre-synaptic glutamate vesicle density. Low glutamate release levels are common in autism, which could explain the reduced expression of the MAP6 protein. Another hypothesis is that less MAP6 can impair the myelin development in oligodendrocytes, which can lead to abnormalities in synaptic function and myelination that could explain the behavioral phenotypes in autism.[17]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000171533 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055407 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Andrieux A, Salin PA, Vernet M, Kujala P, Baratier J, Gory-Fauré S, et al. (September 2002). "The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders". Genes & Development. 16 (18): 2350–2364. doi:10.1101/gad.223302. PMC 187434. PMID 12231625.
  6. ^ "Entrez Gene: MAP6 microtubule-associated protein 6".
  7. ^ Tortosa E, Adolfs Y, Fukata M, Pasterkamp RJ, Kapitein LC, Hoogenraad CC (May 2017). "Dynamic Palmitoylation Targets MAP6 to the Axon to Promote Microtubule Stabilization during Neuronal Polarization". Neuron. 94 (4): 809–825.e7. doi:10.1016/j.neuron.2017.04.042. PMID 28521134. S2CID 5517794.
  8. ^ a b c d Cuveillier C, Boulan B, Ravanello C, Denarier E, Deloulme JC, Gory-Fauré S, et al. (2021-05-05). "Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories". Frontiers in Molecular Neuroscience. 14: 665693. doi:10.3389/fnmol.2021.665693. PMC 8131560. PMID 34025352.
  9. ^ Gory-Fauré S, Windscheid V, Brocard J, Montessuit S, Tsutsumi R, Denarier E, et al. (2014-12-19). "Non-microtubular localizations of microtubule-associated protein 6 (MAP6)". PLOS ONE. 9 (12): e114905. Bibcode:2014PLoSO...9k4905G. doi:10.1371/journal.pone.0114905. PMC 4272302. PMID 25526643.
  10. ^ Cuveillier C, Delaroche J, Seggio M, Gory-Fauré S, Bosc C, Denarier E, et al. (April 2020). "MAP6 is an intraluminal protein that induces neuronal microtubules to coil". Science Advances. 6 (14): eaaz4344. Bibcode:2020SciA....6.4344C. doi:10.1126/sciadv.aaz4344. PMC 7112752. PMID 32270043.
  11. ^ Deloulme JC, Gory-Fauré S, Mauconduit F, Chauvet S, Jonckheere J, Boulan B, et al. (June 2015). "Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth". Nature Communications. 6: 7246. Bibcode:2015NatCo...6.7246D. doi:10.1038/ncomms8246. PMC 4468860. PMID 26037503.
  12. ^ Benardais K, Kasem B, Couegnas A, Samama B, Fernandez S, Schaeffer C, et al. (September 2010). "Loss of STOP protein impairs peripheral olfactory neurogenesis". PLOS ONE. 5 (9): e12753. Bibcode:2010PLoSO...512753B. doi:10.1371/journal.pone.0012753. PMC 2939889. PMID 20856814.
  13. ^ Fournet V, Jany M, Fabre V, Chali F, Orsal D, Schweitzer A, et al. (December 2010). "The deletion of the microtubule-associated STOP protein affects the serotonergic mouse brain network" (PDF). Journal of Neurochemistry. 115 (6): 1579–1594. doi:10.1111/j.1471-4159.2010.07064.x. PMID 20969568. S2CID 14516688.
  14. ^ Dacheux D, Landrein N, Thonnus M, Gilbert G, Sahin A, Wodrich H, et al. (2012-02-15). "A MAP6-related protein is present in protozoa and is involved in flagellum motility". PLOS ONE. 7 (2): e31344. Bibcode:2012PLoSO...731344D. doi:10.1371/journal.pone.0031344. PMC 3280300. PMID 22355359.
  15. ^ Daoust A, Bohic S, Saoudi Y, Debacker C, Gory-Fauré S, Andrieux A, et al. (August 2014). "Neuronal transport defects of the MAP6 KO mouse - a model of schizophrenia - and alleviation by Epothilone D treatment, as observed using MEMRI". NeuroImage. 96: 133–142. doi:10.1016/j.neuroimage.2014.03.071. PMID 24704457. S2CID 17473786.
  16. ^ Gimenez U, Boulan B, Mauconduit F, Taurel F, Leclercq M, Denarier E, et al. (September 2017). "3D imaging of the brain morphology and connectivity defects in a model of psychiatric disorders: MAP6-KO mice". Scientific Reports. 7 (1): 10308. Bibcode:2017NatSR...710308G. doi:10.1038/s41598-017-10544-2. PMC 5583184. PMID 28871106.
  17. ^ a b Wei H, Sun S, Li Y, Yu S (November 2016). "Reduced plasma levels of microtubule-associated STOP/MAP6 protein in autistic patients". Psychiatry Research. 245: 116–118. doi:10.1016/j.psychres.2016.08.024. PMID 27541346. S2CID 34257533.

Further reading

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