Diverse functions of myosin VI elucidated by an isoform-specific ?-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 ?2-linker, that defines specific conformations and hence determines the target selectivity of human myosin VI. The presence of the ?2-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 ?2-linker acts like a molecular switch that assigns myosin VI to distinct endocytic (myosin VI(long)) or migratory (myosin VI(short)) functional roles.

SUBMITTER: Wollscheid HP 

PROVIDER: S-EPMC4964928 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature