Large Protein Assemblies Formed by Multivalent Interactions between Cadherin23 and Harmonin Suggest a Stable Anchorage Structure at the Tip Link of Stereocilia

Abstract

Background: How the root of stereocilia tip link is designed to withstand mechanical stretching is poorly understood. Results: Cadherin23 tail and harmonin form polymeric protein assemblies via nonsynergistic, multisite interactions. Conclusion: The cadherin23 tail/harmonin/actin filament polymer can account for the mechanic strength required by the root of upper tip link. Significance: The findings of this study suggest a mechanism for constructing a strong root for the stereocilia tip link.

Structural plasticity of the HHD2 domain of whirlin

“…We recently showed that in solution, these two N-terminal PDZ domains form a transient supramodule, increasing significantly the affinity of the individual PDZ for one of its cytoplasmic partners (sans) [14]. It has also been proposed that whirlin and other cytoplasmic proteins involved in hearing form dimers in hair cells [21,24]. It is possible that the molecular interactions involving HHD2 are related to the function of the C-terminal isoform of whirlin, localized at the tip of mature stereocilia and involved in interaction with actin-related proteins [22].…”

MyTH4-FERM myosins in the assembly and maintenance of actin-based protrusions

“…At upper tip-link densities, Myo7a uses its N-terminal MyTH4-FERM domain to interact directly with the ankyrin repeat protein, SANS [6,59], which in turn interacts with the actin-bundling PDZ scaffolding protein, harmonin/USH1C (isoform b) [59,60]. The Myo7a/SANS/USH1C complex interacts with the cytoplasmic domain of CDH23 through the N-terminal PDZ domains of USH1C [59,61–65]. Although the only direct cargo binding interaction in this case is with SANS, Myo7a is indirectly responsible for the localization of USH1C [62].…”

Myosin VII, USH1C, and ANKS4B or USH1G Together Form Condensed Molecular Assembly via Liquid-Liquid Phase Separation

“…It should be noted that, in addition to the 3 specific pairs of interactions investigated for each complex in this study, other protein-protein interactions associated with the MYO7A/USH1C/ USH1G and MYO7B/USH1C/ANKS4B complexes may further promote the dense tip-link complex condensates formation. For example, the cochlea-specific exon68 of CDH23, which was shown to facilitate the dimerization of CDH23 CT, has the capacity to form large protein assemblies with USH1C (Wu et al, 2012). Both USH1C and USH1G were reported to have a tendency to self-associate and form oligomers (Bahloul et al, 2017;Yan et al, 2010;Yu et al, 2017).…”