Unconventional myosin-VI

Unconventional myosin-VI, is a protein that in humans is coded for by MYO6.^[5] Unconventional myosin-VI is a myosin molecular motor involved in intracellular vesicle and organelle transport.^[6]

MYO6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2N11, 2N13, 2N0Z, 2N10, 2N12
Identifiers
Aliases	MYO6, DFNA22, DFNB37, myosin VI, Myo6-008, Myo6-007
External IDs	OMIM: 600970; MGI: 104785; HomoloGene: 56417; GeneCards: MYO6; OMA:MYO6 - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6q14.1 Start 75,749,201 bp[1] End 75,919,537 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 E1|9 43.98 cM Start 80,072,313 bp[2] End 80,219,011 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in amniotic fluid internal globus pallidus corpus callosum sural nerve external globus pallidus pancreatic ductal cell inferior ganglion of vagus nerve pars reticulata subthalamic nucleus renal medulla Top expressed in olfactory epithelium neural layer of retina yolk sac right kidney human kidney utricle epithelium of small intestine ileum Ileal epithelium vestibular sensory epithelium More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytoskeletal motor activity actin filament binding ATP binding calmodulin binding protein binding minus-end directed microfilament motor activity ADP binding actin binding nucleotide binding cadherin binding identical protein binding Cellular component myosin complex nucleus intracellular membrane-bounded organelle cell projection ruffle membrane RNA polymerase II, holoenzyme nucleoplasm lysosomal membrane perinuclear region of cytoplasm clathrin-coated endocytic vesicle apical part of cell clathrin-coated vesicle membrane ruffle cytosol extracellular exosome membrane clathrin-coated pit filamentous actin plasma membrane nuclear membrane cytoplasm cell cortex microvillus Golgi apparatus unconventional myosin complex endocytic vesicle cytoplasmic vesicle actin filament protein-containing complex clathrin-coated vesicle filopodium Biological process intracellular protein transport actin filament-based movement regulation of secretion hearing positive regulation of transcription by RNA polymerase II protein transport endocytosis DNA damage response, signal transduction by p53 class mediator transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4646 17920 Ensembl ENSG00000196586 ENSMUSG00000033577 UniProt Q9UM54 Q64331 RefSeq (mRNA) NM_001300899 NM_004999 NM_001368136 NM_001368137 NM_001368138 NM_001368139 NM_001368140 NM_001368865 NM_001368866 NM_001039546 NM_008662 RefSeq (protein) NP_001287828 NP_004990 NP_001355065 NP_001355066 NP_001355067 NP_001355068 NP_001355069 NP_001355794 NP_001355795 n/a Location (UCSC) Chr 6: 75.75 – 75.92 Mb Chr 9: 80.07 – 80.22 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Human myosin-VI contains a N-terminal myosin head domain (residues 59–759), two coiled coil motifs (residues 902–984 and 986–1009 respectively), and a C-terminal myosin VI cargo binding domain (residues 1177–1267).^[7]

Function

Unconventional myosin-VI is unique because it travels in the opposite direction of other myosins, towards the negative end of actin filaments. Myosin-VI follows the same structure as other myosin but with two unique "inserts" allowing for its diversified properties. One insert is called the "reverse gear" and is responsible for its movement towards the negative end of actin filaments. The reverse gear is located on the neck region of the myosin and acts as a reorienting device for the lever arm to move backwards after myosin movement. The second insert assists in regulating ATP enzyme activity located in the motor head domain.^[8]

There are 3 amino acid binding sites essential for myosin-VI's interactions, Arg-Arg-Leu and Trp-Trp-Tyr in the tail region and Met-Ile-Sec in the helix. The Arg-Arg-Leu amino acid segment (abbreviated RRL) takes part in ubiquitin interactions while Trp-Trp-Tyr (abbreviated WWY) assists in interactions with DAB2. Myosin-VI's Met-Ile-Sec bonding interactions are limited to the myosin-VI long isoform but interact with clathrin in endocytosis.

Myosin-VI long isoform is formed by the inclusion of exon 31, adding an addition alpha-helix, restriction RRL interactions. Myosin-VI long struggles to interact with ubiquitin chains and GIPC1 due to this structural formation, however, increases attractivity to clathrin. Myosin-VI's structural flexibility provides a great width in interaction ability with its environment and interactors.^[9]

Interactions

MYO6 has been shown to interact with GIPC1,^[10][11] DAB2.,^[12][13] ubiquitin,^[14] and clathrin.^[15] Myosin VI, being a motor protein, focuses its interactions by moving along actin filaments. This however does not limit its functions, because MYO6 is heavily involved in cytokinesis, creation of membrane compartments, and the regulation and organization of actin filaments.^[16]

Clinical significance

Mutations in the MYO6 gene are associated with hearing loss.^[17] MYO6 has also been found to be involved in many events in spermiogenesis in numerous different creatures. In common fruit flies (Drosophila), the myosin-VI ortholog controls the sterility of males by organization of actin involved in spermatid individualization. This same ortholog in roundworms (C. elegans) regulates the separation of cytosol in spermatid formation due to its influence in cytokinesis. In mice, this ortholog will control specialization and membrane compartment creation.^[16]

References

1. GRCh38: Ensembl release 89: ENSG00000196586 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000033577 – 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. "MYO6 - Unconventional myosin-VI - Homo sapiens (Human) - MYO6 gene & protein". www.uniprot.org. Retrieved 7 April 2022.
6. "Entrez Gene: MYO6 myosin VI".
7. "Protein: MYO6_HUMAN (Q9UM54)". Pfam. European Molecular Biology Laboratory.
8. Zakrzewski P, Lenartowska M, Buss F (March 2021). "Diverse functions of myosin VI in spermiogenesis". Histochemistry and Cell Biology. 155 (3): 323–340. doi:10.1007/s00418-020-01954-x. PMC 8021524. PMID 33386429.
9. Magistrati E, Polo S (April 2021). "Myomics: myosin VI structural and functional plasticity". Current Opinion in Structural Biology. 67: 33–40. doi:10.1016/j.sbi.2020.09.005. hdl:2434/801699. PMID 33053464. S2CID 222421080.
10. Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
11. Aschenbrenner L, Lee T, Hasson T (July 2003). "Myo6 facilitates the translocation of endocytic vesicles from cell peripheries". Molecular Biology of the Cell. 14 (7): 2728–2743. doi:10.1091/mbc.E02-11-0767. PMC 165672. PMID 12857860.
12. Morris SM, Arden SD, Roberts RC, Kendrick-Jones J, Cooper JA, Luzio JP, Buss F (May 2002). "Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton". Traffic. 3 (5): 331–341. doi:10.1034/j.1600-0854.2002.30503.x. PMID 11967127. S2CID 25079713.
13. Inoue A, Sato O, Homma K, Ikebe M (March 2002). "DOC-2/DAB2 is the binding partner of myosin VI". Biochemical and Biophysical Research Communications. 292 (2): 300–307. doi:10.1006/bbrc.2002.6636. PMID 11906161.
14. He F, Wollscheid HP, Nowicka U, Biancospino M, Valentini E, Ehlinger A, et al. (March 2016). "Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains". Cell Reports. 14 (11): 2683–2694. doi:10.1016/j.celrep.2016.01.079. PMC 4805485. PMID 26971995.
15. Biancospino M, Buel GR, Niño CA, Maspero E, Scotto di Perrotolo R, Raimondi A, et al. (October 2019). "Clathrin light chain A drives selective myosin VI recruitment to clathrin-coated pits under membrane tension". Nature Communications. 10 (1): 4974. Bibcode:2019NatCo..10.4974B. doi:10.1038/s41467-019-12855-6. PMC 6823378. PMID 31672988.
16. Sweeney HL, Houdusse A (February 2007). "What can myosin VI do in cells?". Current Opinion in Cell Biology. 19 (1): 57–66. doi:10.1016/j.ceb.2006.12.005. PMID 17175153.
17. Friedman TB, Belyantseva IA, Frolenkov GI (2020). "Myosins and Hearing". Myosins. Advances in Experimental Medicine and Biology. Vol. 1239. pp. 317–330. doi:10.1007/978-3-030-38062-5_13. ISBN 978-3-030-38061-8. PMID 32451864. S2CID 218894008.

Further reading

• Buss F, Luzio JP, Kendrick-Jones J (November 2001). "Myosin VI, a new force in clathrin mediated endocytosis". FEBS Letters. 508 (3): 295–299. doi:10.1016/S0014-5793(01)03065-4. PMID 11728438. S2CID 44995651.
• Hasson T (September 2003). "Myosin VI: two distinct roles in endocytosis". Journal of Cell Science. 116 (Pt 17): 3453–3461. doi:10.1242/jcs.00669. PMID 12893809.
• Avraham KB, Hasson T, Steel KP, Kingsley DM, Russell LB, Mooseker MS, et al. (December 1995). "The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells". Nature Genetics. 11 (4): 369–375. doi:10.1038/ng1295-369. PMID 7493015. S2CID 29467878.
• Bement WM, Hasson T, Wirth JA, Cheney RE, Mooseker MS (July 1994). "Identification and overlapping expression of multiple unconventional myosin genes in vertebrate cell types". Proceedings of the National Academy of Sciences of the United States of America. 91 (14): 6549–6553. Bibcode:1994PNAS...91.6549B. doi:10.1073/pnas.91.14.6549. PMC 44240. PMID 8022818.
• Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Miyajima N, et al. (April 1997). "Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research. 4 (2): 141–150. doi:10.1093/dnares/4.2.141. PMID 9205841.
• Avraham KB, Hasson T, Sobe T, Balsara B, Testa JR, Skvorak AB, et al. (August 1997). "Characterization of unconventional MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice". Human Molecular Genetics. 6 (8): 1225–1231. doi:10.1093/hmg/6.8.1225. PMID 9259267.
• Buss F, Kendrick-Jones J, Lionne C, Knight AE, Côté GP, Paul Luzio J (December 1998). "The localization of myosin VI at the golgi complex and leading edge of fibroblasts and its phosphorylation and recruitment into membrane ruffles of A431 cells after growth factor stimulation". The Journal of Cell Biology. 143 (6): 1535–1545. doi:10.1083/jcb.143.6.1535. PMC 2132970. PMID 9852149.
• Wells AL, Lin AW, Chen LQ, Safer D, Cain SM, Hasson T, et al. (September 1999). "Myosin VI is an actin-based motor that moves backwards". Nature. 401 (6752): 505–508. Bibcode:1999Natur.401..505W. doi:10.1038/46835. PMID 10519557. S2CID 1420305.
• Buss F, Arden SD, Lindsay M, Luzio JP, Kendrick-Jones J (July 2001). "Myosin VI isoform localized to clathrin-coated vesicles with a role in clathrin-mediated endocytosis". The EMBO Journal. 20 (14): 3676–3684. doi:10.1093/emboj/20.14.3676. PMC 125554. PMID 11447109.
• Melchionda S, Ahituv N, Bisceglia L, Sobe T, Glaser F, Rabionet R, et al. (September 2001). "MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss". American Journal of Human Genetics. 69 (3): 635–640. doi:10.1086/323156. PMC 1235492. PMID 11468689.
• Yoshimura M, Homma K, Saito J, Inoue A, Ikebe R, Ikebe M (October 2001). "Dual regulation of mammalian myosin VI motor function". The Journal of Biological Chemistry. 276 (43): 39600–39607. doi:10.1074/jbc.M105080200. PMID 11517222.
• Rock RS, Rice SE, Wells AL, Purcell TJ, Spudich JA, Sweeney HL (November 2001). "Myosin VI is a processive motor with a large step size". Proceedings of the National Academy of Sciences of the United States of America. 98 (24): 13655–13659. Bibcode:2001PNAS...9813655R. doi:10.1073/pnas.191512398. PMC 61096. PMID 11707568.
• Inoue A, Sato O, Homma K, Ikebe M (March 2002). "DOC-2/DAB2 is the binding partner of myosin VI". Biochemical and Biophysical Research Communications. 292 (2): 300–307. doi:10.1006/bbrc.2002.6636. PMID 11906161.
• Morris SM, Arden SD, Roberts RC, Kendrick-Jones J, Cooper JA, Luzio JP, Buss F (May 2002). "Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton". Traffic. 3 (5): 331–341. doi:10.1034/j.1600-0854.2002.30503.x. PMID 11967127. S2CID 25079713.
• Wu H, Nash JE, Zamorano P, Garner CC (August 2002). "Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking". The Journal of Biological Chemistry. 277 (34): 30928–30934. doi:10.1074/jbc.M203735200. PMID 12050163.
• Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, et al. (May 2003). "Mutations of MYO6 are associated with recessive deafness, DFNB37". American Journal of Human Genetics. 72 (5): 1315–1322. doi:10.1086/375122. PMC 1180285. PMID 12687499.
• Aschenbrenner L, Lee T, Hasson T (July 2003). "Myo6 facilitates the translocation of endocytic vesicles from cell peripheries". Molecular Biology of the Cell. 14 (7): 2728–2743. doi:10.1091/mbc.E02-11-0767. PMC 165672. PMID 12857860.

External links

• Overview of all the structural information available in the PDB for UniProt: Q9UM54 (Unconventional myosin-VI) at the PDBe-KB.