Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction.

Abstract	In the most accepted model for hair cell mechanotransduction, a cluster of myosin motors located at the stereocilia upper tip-link density (UTLD) keeps the tip-link under tension at rest. Both myosin VIIa (MYO7A) and myosin 1c have been implicated in mechanotransduction based on functional studies. However, localization studies are conflicting, leaving open the question of which myosin localizes at the UTLD and generates the tip-link resting tension. Using immunofluorescence, we now show that MYO7A and sans, a MYO7A-interacting protein, cluster at the UTLD. Analysis of the immunofluorescence intensity indicates that eight or more MYO7A molecules are present at each UTLD, consistent with a direct role for MYO7A in maintaining tip-link tension. MYO7A and sans localization at the UTLD is confirmed by transfection of hair cells with GFP-tagged constructs for these proteins. Cotransfection studies in a heterologous system show that MYO7A, sans, and the UTLD protein harmonin-b form a tripartite complex and that each protein is capable of interacting with one another independently. We propose that MYO7A, sans, and harmonin-b form the core components of the UTLD molecular complex. In this complex, MYO7A is likely the motor element that pulls on CDH23 to exert tension on the tip-link.
Authors	M'hamed Grati, Bechara Kachar
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 28 Pg. 11476-81 (Jul 12 2011) ISSN: 1091-6490 [Electronic] United States
PMID	21709241 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References	Carrier Proteins Cell Cycle Proteins Cytoskeletal Proteins MYO7A protein, human Multiprotein Complexes Myo7a protein, mouse Myo7a protein, rat Myosin VIIa Nerve Tissue Proteins Recombinant Fusion Proteins Sans protein, mouse Ush1c protein, mouse Green Fluorescent Proteins Myosins
Topics	Amino Acid Sequence Animals COS Cells Carrier Proteins (chemistry, genetics, metabolism) Cell Cycle Proteins Chlorocebus aethiops Cilia (metabolism, ultrastructure) Cytoskeletal Proteins Green Fluorescent Proteins (genetics, metabolism) Guinea Pigs Hair Cells, Vestibular (metabolism, ultrastructure) Humans Mechanotransduction, Cellular (physiology) Mice Mice, Mutant Strains Microscopy, Electron, Scanning Microscopy, Fluorescence Molecular Sequence Data Multiprotein Complexes Myosin VIIa Myosins (chemistry, genetics, metabolism) Nerve Tissue Proteins (chemistry, genetics, metabolism) Organ of Corti (metabolism, ultrastructure) Protein Interaction Domains and Motifs Rats Recombinant Fusion Proteins (chemistry, genetics, metabolism) Sequence Homology, Amino Acid Usher Syndromes (physiopathology)

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