TY - JOUR
T1 - Diverse functions of myosin VI elucidated by an isoform-specific α-helix domain
AU - Wollscheid, Hans Peter
AU - Biancospino, Matteo
AU - He, Fahu
AU - Magistrati, Elisa
AU - Molteni, Erika
AU - Lupia, Michela
AU - Soffientini, Paolo
AU - Rottner, Klemens
AU - Cavallaro, Ugo
AU - Pozzoli, Uberto
AU - Mapelli, Marina
AU - Walters, Kylie J.
AU - Polo, Simona
PY - 2016/4/5
Y1 - 2016/4/5
N2 - 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.
AB - 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.
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U2 - 10.1038/nsmb.3187
DO - 10.1038/nsmb.3187
M3 - Article
VL - 23
SP - 300
EP - 308
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 4
ER -