title: A Myo6 mutation destroys coordination between the myosin heads, revealing new functions of myosin VI in the stereocilia of mammalian inner ear hair cells.
abstract: Myosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in an ENU-generated mouse model, Tailchaser, disrupts myosin VI function. Structural changes in the Tailchaser hair bundles include mislocalization of the kinocilia and branching of stereocilia. Transfection of GFP-labeled myosin VI into epithelial cells and delivery of endocytic vesicles to the early endosome revealed that the mutant phenotype displays disrupted motor function. The actin-activated ATPase rates measured for the D179Y mutation are decreased, and indicate loss of coordination of the myosin VI heads or 'gating' in the dimer form. Proper coordination is required for walking processively along, or anchoring to, actin filaments, and is apparently destroyed by the proximity of the mutation to the nucleotide-binding pocket. This loss of myosin VI function may not allow myosin VI to transport its cargoes appropriately at the base and within the stereocilia, or to anchor the membrane of stereocilia to actin filaments via its cargos, both of which lead to structural changes in the stereocilia of myosin VI-impaired hair cells, and ultimately leading to deafness.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ronna
authors.initials: R
authors.lastname: Hertzano
authors.forename: Ella
authors.initials: E
authors.lastname: Shalit
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Rzadzinska
authors.forename: Amiel A
authors.initials: AA
authors.lastname: Dror
authors.forename: Lin
authors.initials: L
authors.lastname: Song
authors.forename: Uri
authors.initials: U
authors.lastname: Ron
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Tan
authors.forename: Alina Starovolsky
authors.initials: AS
authors.lastname: Shitrit
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Tama
authors.initials: T
authors.lastname: Hasson
authors.forename: Nir
authors.initials: N
authors.lastname: Ben-Tal
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.forename: Martin Hrabe
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002874:Chromosome Mapping; D003638:Deafness / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006199:Hair Cells, Auditory, Inner / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D022161:Transport Vesicles / Q000737:chemistry / Q000378:metabolism
chemical_list: C089785:myosin VI; D000251:Adenosine Triphosphatases; D018995:Myosin Heavy Chains