Abstract
Cadherin linkages between adjacent stereocilia and microvilli are essential for mechanotransduction and maintaining their organization. They are anchored to actin through interaction of their cytoplasmic domains with related tripartite complexes consisting of a class VII myosin and adaptor proteins: Myo7a/SANS/Harmonin in stereocilia and Myo7b/ANKS4B/Harmonin in microvilli. Here, we determine high-resolution structures of Myo7a and Myo7b C-terminal MyTH4-FERM domain (MF2) and unveil how they recognize harmonin using a novel binding mode. Systematic definition of interactions between domains of the tripartite complex elucidates how the complex assembles and prevents possible self-association of harmonin-a. Several Myo7a deafness mutants that map to the surface of MF2 disrupt harmonin binding, revealing the molecular basis for how they impact the formation of the tripartite complex and disrupt mechanotransduction. Our results also suggest how switching between different harmonin isoforms can regulate the formation of networks with Myo7a motors and coordinate force sensing in stereocilia.
Highlights
Cadherin linkages between adjacent stereocilia and microvilli are essential for mechanotransduction and maintaining their organization
While Myo7a and harmonin are found to localize along the length of stereocilia, all three Usher proteins are concentrated at UTLD, where they associate with the tip link and regulate the function of MET13–15
Several mutations in these proteins and/or cadherin are found to be associated with non-syndromic deafness DFNB and DFNA7, while others result in Usher syndrome type I (USH1), the most severe form of deaf-blindness characterized by profound congenital hearing loss and a prepubertal onset of retinis pigmentosa[4]
Summary
Cadherin linkages between adjacent stereocilia and microvilli are essential for mechanotransduction and maintaining their organization They are anchored to actin through interaction of their cytoplasmic domains with related tripartite complexes consisting of a class VII myosin and adaptor proteins: Myo7a/SANS/Harmonin in stereocilia and Myo7b/ANKS4B/Harmonin in microvilli. The cadherin-based connections between stereocilia or microvilli are essential for the formation of mechanically integrated bundles of these projections that must withstand shear stresses imposed on them This is achieved by anchoring the cytoplasmic domains of cadherins to the actin cytoskeleton via similar tripartite complexes consisting of a class-VII myosin motor (Myo7) and two modular adaptor proteins[3,4,5] (Fig. 1). Deletions of, any component of this tripartite complex results in disorganization of apical microvilli[3,5,16]
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