title: Diverse functions of myosin VI elucidated by an isoform-specific α-helix domain.
abstract: Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VI(short) and myosin VI(long), which differ in the C-terminal region. Their physiological and pathological roles remain unknown. Here we identified an isoform-specific regulatory helix, named the α2-linker, that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the α2-linker structurally defines a new clathrin-binding domain that is unique to myosin VI(long) and masks the known RRL interaction motif. This finding is relevant to ovarian cancer, in which alternative myosin VI splicing is aberrantly regulated, and exon skipping dictates cell addiction to myosin VI(short) in tumor-cell migration. The RRL interactor optineurin contributes to this process by selectively binding myosin VI(short). Thus, the α2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VI(long)) or migratory (myosin VI(short)) functional roles.
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20139, Italy.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Wollscheid
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20139, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Biancospino
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Fahu
authors.initials: F
authors.lastname: He
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20139, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Magistrati
authors.affiliation: Computational Biology, Scientific Institute IRCCS E.MEDEA, Bosisio Parini 23842, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Molteni
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan 20141, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Lupia
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20139, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Soffientini
authors.affiliation: Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.|Braunschweig University of Technology, 38106 Braunschweig, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Rottner
authors.affiliation: Molecular Medicine Program, European Institute of Oncology, Milan 20141, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallaro
authors.affiliation: Computational Biology, Scientific Institute IRCCS E.MEDEA, Bosisio Parini 23842, Italy.
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mapelli
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Kylie J
authors.initials: KJ
authors.lastname: Walters
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan 20139, Italy.|Dipartimento di oncologia ed emato-oncologia (DIPO), Universita' degli Studi di Milano, Milan 20122, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Polo
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D002966:Clathrin / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018995:Myosin Heavy Chains / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D060066:Protein Interaction Maps; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D002966:Clathrin; D020033:Protein Isoforms; C089785:myosin VI; D018995:Myosin Heavy Chains