Unconventional myosin-VI explained

Unconventional myosin-VI, is a protein that in humans is coded for by MYO6.^[1] Unconventional myosin-VI is a myosin molecular motor involved in intracellular vesicle and organelle transport.^[2]

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).^[3]

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.^[4]

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.^[5]

Interactions

MYO6 has been shown to interact with GIPC1,^{[6] [7]} DAB2.,^{[8] [9]} ubiquitin,^[10] and clathrin.^[11] 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.^[12]

Clinical significance

Mutations in the MYO6 gene are associated with hearing loss.^[13] 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.

Further reading

• Buss F, Luzio JP, Kendrick-Jones J . Myosin VI, a new force in clathrin mediated endocytosis . FEBS Letters . 508 . 3 . 295–299 . November 2001 . 11728438 . 10.1016/S0014-5793(01)03065-4 . 44995651 . free .
• Hasson T . Myosin VI: two distinct roles in endocytosis . Journal of Cell Science . 116 . Pt 17 . 3453–3461 . September 2003 . 12893809 . 10.1242/jcs.00669 . free .
• Avraham KB, Hasson T, Steel KP, Kingsley DM, Russell LB, Mooseker MS, Copeland NG, Jenkins NA . 6 . 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 . December 1995 . 7493015 . 10.1038/ng1295-369 . 29467878 .
• Bement WM, Hasson T, Wirth JA, Cheney RE, Mooseker MS . 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 . July 1994 . 8022818 . 44240 . 10.1073/pnas.91.14.6549 . free . 1994PNAS...91.6549B .
• Nagase T, Ishikawa K, Nakajima D, Ohira M, Seki N, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . 6 . 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 . April 1997 . 9205841 . 10.1093/dnares/4.2.141 . free .
• Avraham KB, Hasson T, Sobe T, Balsara B, Testa JR, Skvorak AB, Morton CC, Copeland NG, Jenkins NA . 6 . 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 . August 1997 . 9259267 . 10.1093/hmg/6.8.1225 . free .
• Buss F, Kendrick-Jones J, Lionne C, Knight AE, Côté GP, Paul Luzio J . 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 . December 1998 . 9852149 . 2132970 . 10.1083/jcb.143.6.1535 .
• Wells AL, Lin AW, Chen LQ, Safer D, Cain SM, Hasson T, Carragher BO, Milligan RA, Sweeney HL . 6 . Myosin VI is an actin-based motor that moves backwards . Nature . 401 . 6752 . 505–508 . September 1999 . 10519557 . 10.1038/46835 . 1420305 . 1999Natur.401..505W .
• Buss F, Arden SD, Lindsay M, Luzio JP, Kendrick-Jones J . Myosin VI isoform localized to clathrin-coated vesicles with a role in clathrin-mediated endocytosis . The EMBO Journal . 20 . 14 . 3676–3684 . July 2001 . 11447109 . 125554 . 10.1093/emboj/20.14.3676 .
• Melchionda S, Ahituv N, Bisceglia L, Sobe T, Glaser F, Rabionet R, Arbones ML, Notarangelo A, Di Iorio E, Carella M, Zelante L, Estivill X, Avraham KB, Gasparini P . 6 . 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 . September 2001 . 11468689 . 1235492 . 10.1086/323156 .
• Yoshimura M, Homma K, Saito J, Inoue A, Ikebe R, Ikebe M . Dual regulation of mammalian myosin VI motor function . The Journal of Biological Chemistry . 276 . 43 . 39600–39607 . October 2001 . 11517222 . 10.1074/jbc.M105080200 . free .
• Rock RS, Rice SE, Wells AL, Purcell TJ, Spudich JA, Sweeney HL . 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 . November 2001 . 11707568 . 61096 . 10.1073/pnas.191512398 . free . 2001PNAS...9813655R .
• Inoue A, Sato O, Homma K, Ikebe M . DOC-2/DAB2 is the binding partner of myosin VI . Biochemical and Biophysical Research Communications . 292 . 2 . 300–307 . March 2002 . 11906161 . 10.1006/bbrc.2002.6636 .
• Morris SM, Arden SD, Roberts RC, Kendrick-Jones J, Cooper JA, Luzio JP, Buss F . Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton . Traffic . 3 . 5 . 331–341 . May 2002 . 11967127 . 10.1034/j.1600-0854.2002.30503.x . 25079713 .
• Wu H, Nash JE, Zamorano P, Garner CC . 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 . August 2002 . 12050163 . 10.1074/jbc.M203735200 . free .
• Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, Mohiddin SA, Fananapazir L, Caruso RC, Husnain T, Khan SN, Riazuddin S, Griffith AJ, Friedman TB, Wilcox ER . 6 . Mutations of MYO6 are associated with recessive deafness, DFNB37 . American Journal of Human Genetics . 72 . 5 . 1315–1322 . May 2003 . 12687499 . 1180285 . 10.1086/375122 .
• Aschenbrenner L, Lee T, Hasson T . Myo6 facilitates the translocation of endocytic vesicles from cell peripheries . Molecular Biology of the Cell . 14 . 7 . 2728–2743 . July 2003 . 12857860 . 165672 . 10.1091/mbc.E02-11-0767 .

Notes and References

1. Web site: MYO6 - Unconventional myosin-VI - Homo sapiens (Human) - MYO6 gene & protein . www.uniprot.org . 7 April 2022 . en.
2. Web site: Entrez Gene: MYO6 myosin VI.
3. Web site: Protein: MYO6_HUMAN (Q9UM54) . Pfam . European Molecular Biology Laboratory .
4. Zakrzewski P, Lenartowska M, Buss F . Diverse functions of myosin VI in spermiogenesis . Histochemistry and Cell Biology . 155 . 3 . 323–340 . March 2021 . 33386429 . 8021524 . 10.1007/s00418-020-01954-x .
5. Magistrati E, Polo S . Myomics: myosin VI structural and functional plasticity . Current Opinion in Structural Biology . 67 . 33–40 . April 2021 . 33053464 . 10.1016/j.sbi.2020.09.005 . 222421080 . free . 2434/801699 . free .
6. Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D . 6 . Large-scale mapping of human protein-protein interactions by mass spectrometry . Molecular Systems Biology . 3 . 1 . 89 . 2007 . 17353931 . 1847948 . 10.1038/msb4100134 .
7. Aschenbrenner L, Lee T, Hasson T . Myo6 facilitates the translocation of endocytic vesicles from cell peripheries . Molecular Biology of the Cell . 14 . 7 . 2728–2743 . July 2003 . 12857860 . 165672 . 10.1091/mbc.E02-11-0767 .
8. Morris SM, Arden SD, Roberts RC, Kendrick-Jones J, Cooper JA, Luzio JP, Buss F . Myosin VI binds to and localises with Dab2, potentially linking receptor-mediated endocytosis and the actin cytoskeleton . Traffic . 3 . 5 . 331–341 . May 2002 . 11967127 . 10.1034/j.1600-0854.2002.30503.x . 25079713 .
9. Inoue A, Sato O, Homma K, Ikebe M . DOC-2/DAB2 is the binding partner of myosin VI . Biochemical and Biophysical Research Communications . 292 . 2 . 300–307 . March 2002 . 11906161 . 10.1006/bbrc.2002.6636 .
10. He F, Wollscheid HP, Nowicka U, Biancospino M, Valentini E, Ehlinger A, Acconcia F, Magistrati E, Polo S, Walters KJ . 6 . Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains . Cell Reports . 14 . 11 . 2683–2694 . March 2016 . 26971995 . 4805485 . 10.1016/j.celrep.2016.01.079 .
11. Biancospino M, Buel GR, Niño CA, Maspero E, Scotto di Perrotolo R, Raimondi A, Redlingshöfer L, Weber J, Brodsky FM, Walters KJ, Polo S . 6 . Clathrin light chain A drives selective myosin VI recruitment to clathrin-coated pits under membrane tension . Nature Communications . 10 . 1 . 4974 . October 2019 . 31672988 . 6823378 . 10.1038/s41467-019-12855-6 . 2019NatCo..10.4974B .
12. Sweeney HL, Houdusse A . What can myosin VI do in cells? . Current Opinion in Cell Biology . 19 . 1 . 57–66 . February 2007 . 17175153 . 10.1016/j.ceb.2006.12.005 .
13. Book: Friedman TB, Belyantseva IA, Frolenkov GI . Myosins . Myosins and Hearing . Advances in Experimental Medicine and Biology . 1239 . 317–330 . 2020 . 32451864 . 10.1007/978-3-030-38062-5_13 . 978-3-030-38061-8 . 218894008 .