Myosin 7 and its adaptors link cadherins to actin

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.

The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complex

“…Of note, the causative genes for three USH1 subtypes (USH1E, USH1K and USH1H) still have not been identified, suggesting that more Usher complex components may remain to be discovered (17)(18)(19). A similar situation is seen with the IMAC; structure-function studies of this complex clearly point towards the idea that the full interactome is not yet known (5,20,21).…”

Regulation of actin-based apical structures on epithelial cells

“…1B). Here, heterotypic extracellular linkages occur near the tips of microvilli between protocadherin PCDH24 (encoded by CDHR2) and mucin-like protocadherin MLPCDH (encoded by CDHR5) to form links of 50 nm width (Crawley et al, 2014a(Crawley et al, , 2016Li et al, 2016;Yu et al, 2017). The cytoplasmic tail of PCDH24 binds USH1C (harmonin) and forms a ternary linkage with the SANS homolog ANKS4B to link to the MyTH4-FERM domains of Myo7b.…”

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

“…Immunostaining studies showed that Myosin VIIA (MYO7A), USH1G (also known as Sans), and USH1C (also known as Harmonin or autoimmune enteropathy-related 75-kDa antigen ) are located at the UTLD, suggesting that they are involved in the electron-dense plaque formation, although the mechanism underlying the dense assembly formation is not understood (Grati and Kachar, 2011;Grillet et al, 2009). MYO7A, USH1G, and USH1C form a very stable tripartite complex via several pairs of specific interactions (Adato et al, 2005;Li et al, 2017;Pan and Zhang, 2012;Wu et al, 2011;Yan et al, 2010;Yu et al, 2017). The cytoplasmic tail (CT) of CDH23 interacts with USH1C (Pan et al, 2009;Siemens et al, 2002), thus linking the tail of the upper tip-link to UTLD ( Figure 1A).…”

“…The cadherin-related family member 2 (CDHR2, also known as protocadherin 24) and cadherin-related family member 5 (CDHR5, also known as mucin-like protocadherin) interact in trans to form the filamentous tip-link (Crawley et al, 2014b). The CT of CDHR2 is coupled to the actin filaments via a tripartite complex composed of Myosin VIIB (MYO7B), USH1C, and ANKS4B (Crawley et al, 2014b(Crawley et al, , 2016Li et al, 2016aLi et al, , 2017Weck et al, 2016;Yu et al, 2017).…”