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User:MdMcAlister/Protein targeting

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This article deals with protein targeting in eukaryotes except where noted.

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell.[1] Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion.[1] Information contained in the protein itself directs this delivery process.[2] Correct sorting is crucial for the cell; errors have been linked to multiple disease-states.[3][4]

History

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Günter Blobel, awarded the 1999 Nobel Prize in Physiology for his discovery that proteins contain intrinsic signal sequences.

In 1970, Günter Blobel conducted experiments on the translocation of proteins across membranes. Blobel, then an assistant professor at Rockefeller University, built upon the work of his colleague George Palade.[5] Palade had previously demonstrated that non-secreted proteins were translated by free ribosomes in the cytosol, while secreted proteins (and target proteins, in general) were translated by ribosomes bound to the endoplasmic reticulum.[5] Candidate explanations at the time postulated a processing difference between free and ER-bound ribosomes, but Blobel hypothesized that protein targeting relied on characteristics inherent to the proteins, rather than a difference in ribosomes. Supporting his hypothesis, Blobel discovered that many proteins have a short amino acid sequence at one end that functions like a postal code specifying an intracellular or extracellular destination.[2] He described these short sequences (generally 13 to 36 amino acids residues)[1] as signal peptides or signal sequences and was awarded the 1999 Nobel prize in Physiology for his findings.[6]

Signal peptides

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Main article: Signal peptide

Signal peptides serve as targeting signals, enabling cellular transport machinery to direct proteins to specific intracellular or extracellular locations. While no consensus sequence has been identified for signal peptides, many nonetheless possess a characteristic tripartite structure[1]:

  1. A positively charged, hydrophilic region near the N-terminal.
  2. A span of 10 to 15 hydrophobic amino acids near the middle of the signal peptide.
  3. A slightly polar region near the C-terminal, typically favoring amino acids with smaller side chains at positions approaching the cleavage site.

After a protein has reached its destination, the signal peptide is generally cleaved by a signal peptidase.[1] Consequently, most mature proteins do not contain signal peptides. While most signal peptides are found at the N-terminal, in peroxisomes the targeting sequence is located on the C-terminal extension.[7] Unlike signal peptides, signal patches are composed by amino acid residues that are discontinuous in the primary sequence but become functional when folding brings them together on the protein surface.[8] Unlike most signal sequences, signal patches are not cleaved after sorting is complete.[9] In addition to intrinsic signaling sequences, protein modifications like glycosylations can also induce targeting to specific intracellular or extra cellular regions.

Protein translocation

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Further information: translocon

Since the translation of mRNA into protein by a ribosome takes place within the cytosol, proteins destined for secretion or a specific organelle must be translocated[10]. This process can occur during translation, known as co-translational translocation, or after translation is complete, known as post-translational translocation.[11]

Co-translational translocation

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Most secretory and membrane-bound proteins are co-translationally translocated. Proteins that reside in the endoplasmic reticulum (ER), golgi or endosomes also use the co-translational translocation pathway. This process begins while the protein is being synthesized on the ribosome, when a signal recognition particle (SRP) recognizes an N-terminal signal peptide of the nascent protein.[12] Binding of the SRP temporarily pauses synthesis while the ribosome-protein complex is transferred to an SRP receptor on the ER in eukaryotes, and the plasma membrane in prokaryotes.[13] There, the nascent protein is inserted into the translocon, a membrane-bound protein conducting channel composed of the Sec61 translocation complex in eukaryotes, and the homologous SecYEG complex in prokaryotes.[14] In secretory proteins and type I transmembrane proteins, the signal sequence is immediately cleaved from the nascent polypeptide once it has been translocated into the membrane of the ER (eukaryotes) or plasma membrane (prokaryotes) by signal peptidase. The signal sequence of type II membrane proteins and some polytopic membrane proteins are not cleaved off and therefore are referred to as signal anchor sequences. Within the ER, the protein is first covered by a chaperone protein to protect it from the high concentration of other proteins in the ER, giving it time to fold correctly. Once folded, the protein is modified as needed (for example, by glycosylation), then transported to the Golgi for further processing and goes to its target organelles or is retained in the ER by various ER retention mechanisms.

The amino acid chain of transmembrane proteins, which often are transmembrane receptors, passes through a membrane one or several times. These proteins are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor or signal-anchor sequence.[15] These complex membrane proteins are currently characterized using the same model of targeting that has been developed for secretory proteins. However, many complex multi-transmembrane proteins contain structural aspects that do not fit this model. Seven transmembrane G-protein coupled receptors (which represent about 5% of the genes in humans) mostly do not have an amino-terminal signal sequence. In contrast to secretory proteins, the first transmembrane domain acts as the first signal sequence, which targets them to the ER membrane. This also results in the translocation of the amino terminus of the protein into the ER membrane lumen. This translocation, which has been demonstrated with opsin with in vitro experiments,[16][17] breaks the usual pattern of "co-translational" translocation which has always held for mammalian proteins targeted to the ER. A great deal of the mechanics of transmembrane topology and folding remains to be elucidated.

Post-translational translocation

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Even though most secretory proteins are co-translationally translocated, some are translated in the cytosol and later transported to the ER/plasma membrane by a post-translational system. In prokaryotes this process requires certain cofactors such as SecA and SecB and is facilitated by Sec62 and Sec63, two membrane-bound proteins.[18] The Sec63 complex, which is embedded in the ER membrane, causes hydrolysis of ATP, allowing chaperone proteins to bind to an exposed peptide chain and slide the polypeptide into the ER lumen. Once in the lumen the polypeptide chain can be folded properly. This process only occurs in unfolded proteins located in the cytosol.[19]

In addition, proteins targeted to other cellular destinations, such as mitochondria, chloroplasts, or peroxisomes, use specialized post-translational pathways. Proteins targeted for the nucleus are also translocated post-translationally through the addition of a nuclear localization signal (NLS) that promotes passage through the nuclear envelope via nuclear pores.[20]

Sorting of proteins

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Mitochondria

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Three mitochondrial outer membrane receptors are known:

  1. TOM70: Binds to internal targeting peptides and acts as a docking point for cytosolic chaperones.
  2. TOM20: Binds presequences.
  3. TOM22: Binds both presequences and internal targeting peptides.

Peroxisomes

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All peroxisomal proteins are encoded by nuclear genes.[21] To date there are two types of known Peroxisome Targeting Signals (PTS)[22]:

  1. Peroxisome targeting signal 1 (PTS1): a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). The most common PTS1 is serine-lysine-leucine (SKL). Most peroxisomal matrix proteins possess a PTS1 type signal.
  2. Peroxisome targeting signal 2 (PTS2): a nonapeptide located near the N-terminus with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) (where X can be any amino acid).

There are also proteins that possess neither of these signals. Their transport may be based on a so-called "piggy-back" mechanism: such proteins associate with PTS1-possessing matrix proteins and are translocated into the peroxisomal matrix together with them.[23]

Diseases

[edit]

Protein transport is defective in the following genetic diseases:

Bioinformatic tools

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  • Minimotif Miner is a bioinformatics tool that searches protein sequence queries for a known protein targeting sequence motifs.
  • Phobius predicts signal peptides based on a supplied primary sequence.
  • SignalP predicts signal peptide cleavage sites.
  • LOCtree predicts the subcellular localization of proteins.

References

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  1. ^ a b c d e Nelson, David L. (David Lee), 1942-. Lehninger principles of biochemistry. Cox, Michael M.,, Lehninger, Albert L. (Seventh edition ed.). New York, NY. ISBN 978-1-4641-2611-6. OCLC 986827885. {{cite book}}: |edition= has extra text (help)CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  2. ^ a b Blobel, G.; Dobberstein, B. (1975-12-01). "Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma". Journal of Cell Biology. 67 (3): 835–851. doi:10.1083/jcb.67.3.835. ISSN 0021-9525. PMC 2111658. PMID 811671.{{cite journal}}: CS1 maint: PMC format (link)
  3. ^ Schmidt, Vanessa; Willnow, Thomas E. (2016-02-01). "Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases". Atherosclerosis. 245: 194–199. doi:10.1016/j.atherosclerosis.2015.11.027. ISSN 0021-9150.
  4. ^ Guo, Yusong; Sirkis, Daniel W.; Schekman, Randy (2014-10-11). "Protein Sorting at thetrans-Golgi Network". Annual Review of Cell and Developmental Biology. 30 (1): 169–206. doi:10.1146/annurev-cellbio-100913-013012. ISSN 1081-0706.
  5. ^ a b Leslie, Mitch (2005-08-01). "Lost in translation the signal hypothesis". Journal of Cell Biology. 170 (3): 338–338. doi:10.1083/jcb1703fta1. ISSN 0021-9525. PMC 2254867. PMID 16167405.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ "The Nobel Prize in Physiology or Medicine 1999". NobelPrize.org. Retrieved 2020-09-19.
  7. ^ Wanders, Ronald J.A. (2004). "Metabolic and molecular basis of peroxisomal disorders: A review". American Journal of Medical Genetics. 126A (4): 355–375. doi:10.1002/ajmg.a.20661. ISSN 0148-7299.
  8. ^ Moreira, Irina S.; Fernandes, Pedro A.; Ramos, Maria J. (2007-06-01). "Hot spots-A review of the protein-protein interface determinant amino-acid residues". Proteins: Structure, Function, and Bioinformatics. 68 (4): 803–812. doi:10.1002/prot.21396. ISSN 0887-3585.
  9. ^ Pfeffer, S R; Rothman, J E (1987-06-01). "Biosynthetic Protein Transport and Sorting by the Endoplasmic Reticulum and Golgi". Annual Review of Biochemistry. 56 (1): 829–852. doi:10.1146/annurev.bi.56.070187.004145. ISSN 0066-4154.
  10. ^ Sommer, Maik S.; Schleiff, Enrico (2014-08-01). "Protein Targeting and Transport as a Necessary Consequence of Increased Cellular Complexity". Cold Spring Harbor Perspectives in Biology. 6 (8): a016055. doi:10.1101/cshperspect.a016055. ISSN 1943-0264. PMC 4107987. PMID 25085907.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ Walter, P.; Ibrahimi, I.; Blobel, G. (1981-11-01). "Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein". Journal of Cell Biology. 91 (2): 545–550. doi:10.1083/jcb.91.2.545. ISSN 0021-9525. PMC 2111968. PMID 7309795.{{cite journal}}: CS1 maint: PMC format (link)
  12. ^ Voorhees, Rebecca M; Hegde, Ramanujan S (2016-08-01). "Toward a structural understanding of co-translational protein translocation". Current Opinion in Cell Biology. Cell organelles. 41: 91–99. doi:10.1016/j.ceb.2016.04.009. ISSN 0955-0674.
  13. ^ "Co-translational targeting and translocation of proteins to the endoplasmic reticulum". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1833 (11): 2392–2402. 2013-11-01. doi:10.1016/j.bbamcr.2013.02.021. ISSN 0167-4889.
  14. ^ Mandon, Elisabet C; Trueman, Steven F; Gilmore, Reid (2009-08-01). "Translocation of proteins through the Sec61 and SecYEG channels". Current Opinion in Cell Biology. 21 (4): 501–507. doi:10.1016/j.ceb.2009.04.010. ISSN 0955-0674.
  15. ^ Alberts, Bruce,. Essential cell biology (Fifth edition ed.). New York. ISBN 978-0-393-67953-3. OCLC 1048014962. {{cite book}}: |edition= has extra text (help)CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  16. ^ Kanner EM, Friedlander M, Simon SM. (2003). "Co-translational targeting and translocation of the amino terminus of opsin across the endoplasmic membrane requires GTP but not ATP". J. Biol. Chem. 278 (10): 7920–7926. doi:10.1074/jbc.M207462200. PMID 12486130.
  17. ^ Kanner EM, Klein IK. et al. (2002). "The amino terminus of opsin translocates "posttranslationally" as efficiently as cotranslationally". Biochemistry 41 (24): 7707–7715. doi:10.1021/bi0256882. PMID 12056902.
  18. ^ Rapoport, Tom A. (2007-11). "Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes". Nature. 450 (7170): 663–669. doi:10.1038/nature06384. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)
  19. ^ Lodish, Harvey; Berk, Arnold; Kaiser, Chris; Krieger, Monty; Bretscher, Anthony; Ploegh, Hidde; Amon, Angelika; Martin, Kelsey (2008). Molecular Cell Biology (8th ed.). New York: W.H. Freeman and Company. pp. 591–592. ISBN 978-1-4641-8339-3.
  20. ^ Lange, Allison; Mills, Ryan E.; Lange, Christopher J.; Stewart, Murray; Devine, Scott E.; Corbett, Anita H. (2007-02-23). "Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin α". Journal of Biological Chemistry. 282 (8): 5101–5105. doi:10.1074/jbc.R600026200. ISSN 0021-9258. PMC 4502416. PMID 17170104.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  21. ^ Encyclopedia of biological chemistry. Lennarz, William J.,, Lane, M. Daniel, (Second edition ed.). London. ISBN 978-0-12-378631-9. OCLC 828743403. {{cite book}}: |edition= has extra text (help)CS1 maint: extra punctuation (link) CS1 maint: others (link)
  22. ^ Baerends, Richard J.S.; Faber, Klaas Nico; Kiel, Jan A.K.W.; van der Klei, Ida J.; Harder, Wim; Veenhuis, Marten (2000-07-01). "Sorting and function of peroxisomal membrane proteins". FEMS Microbiology Reviews. 24 (3): 291–301. doi:10.1111/j.1574-6976.2000.tb00543.x. ISSN 1574-6976.
  23. ^ Saryi, Nadal A. Al; Hutchinson, John D.; Al-hejjaj, Murtakab Y.; Sedelnikova, Svetlana; Baker, Patrick; Hettema, Ewald H. (2017-02-17). "Pnc1 piggy-back import into peroxisomes relies on Gpd1 homodimerisation". Scientific Reports. 7 (1): 42579. doi:10.1038/srep42579. ISSN 2045-2322.
  24. ^ "RAB7L1 Interacts with LRRK2 to Modify Intraneuronal Protein Sorting and Parkinson's Disease Risk". Neuron. 77 (3): 425–439. 2013-02-06. doi:10.1016/j.neuron.2012.11.033. ISSN 0896-6273.
  25. ^ Schmidt, Vanessa; Willnow, Thomas E. (2016-02-01). "Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases". Atherosclerosis. 245: 194–199. doi:10.1016/j.atherosclerosis.2015.11.027. ISSN 0021-9150.
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