Conformational switch of harmonin, a submembrane scaffold protein of the hair cell mechanoelectrical transduction machinery

Bahloul, Amel; Pepermans, Elise; Raynal, Bertrand; Wolff, Nicolas; Cordier, Florence; England, Patrick; Nouaille, Sylvie; Baron, Bruno; El-Amraoui, Aziz; Hardelin, Jean‐Pierre; Durand, Dominique; Petit, Christine

doi:10.1002/1873-3468.12729

Cited by 9 publications

(13 citation statements)

References 42 publications

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“…2 i) noncanonical protein–protein interactions, involved in the scaffolding function of HHDs together with the formation of intramolecular supramodules, as illustrated by the HHD-PDZ complex in Harmonin (Fig. 2 d) that tunes the binding affinity of the PDZ towards its partners [ 21 , 23 ].…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic analysis of Harmonin homology domains

et al. 2021

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Background Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of adjacent domains for their own targets. Adding their small size and rather simple fold, HHDs appear as convenient modules to regulate protein–protein interactions in various biological contexts. Surprisingly, only nine HHDs have been detected in six proteins, mainly expressed in sensory neurons. Results Here, we built a profile Hidden Markov Model to screen the entire UniProtKB for new HHD-containing proteins. Every hit was manually annotated, using a clustering approach, confirming that only a few proteins contain HHDs. We report the phylogenetic coverage of each protein and build a phylogenetic tree to trace the evolution of HHDs. We suggest that a HHD ancestor is shared with Paired Amphipathic Helices (PAH) domains, a four-helix bundle partially sharing fold and functional properties. We characterized amino-acid sequences of the various HHDs using pairwise BLASTP scoring coupled with community clustering and manually assessed sequence features among each individual family. These sequence features were analyzed using reported structures as well as homology models to highlight structural motifs underlying HHDs fold. We show that functional divergence is carried out by subtle differences in sequences that automatized approaches failed to detect. Conclusions We provide the first HHD databases, including sequences and conservation, phylogenic trees and a list of HHD variants found in the auditory system, which are available for the community. This case study highlights surprising phylogenetic properties found in orphan domains and will assist further studies of HHDs. We unveil the implication of HHDs in their various binding interfaces using conservation across families and a new protein–protein surface predictor. Finally, we discussed the functional consequences of three identified pathogenic HHD variants involved in Hoyeraal-Hreidarsson syndrome and of three newly reported pathogenic variants identified in patients suffering from Usher Syndrome.

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Section: Resultsmentioning

confidence: 99%

Phylogenetic analysis of Harmonin homology domains

et al. 2021

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“…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). MYO7A, analogous to MYO6 (Yu et al, 2009), has been suggested to undergo cargo binding-induced dimerization (Sakai et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

2019

Cell Reports

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“…The αα-hub domains were recently defined based on a common structural foundation ( 21 ) and originally included the following domains: RCD1, SRO, and TAF4 (RST) from Radical-Induced Cell Death1 (RCD1) ( 21 ); paired amphipathic helix (PAH)1, PAH2, and PAH3 from Sin3 of the Sin3/histone deacetylase corepressor complex ( 25 ); TATA-box associated factor homology (TAFH) (or nervy homology region 1 [NHR1]) from transcription initiation factor TFIID-subunit 4 (TAF4) and eight-twenty-one (ETO) (or MTG8/CBFA2T1) ( 26 ); and nuclear coactivator binding domain (NCBD) (or IRF-binding domain) from CREB binding protein (CBP) ( 27 ) ( Figure 1 , Figure 2 , Figure 3 , A – D ). In addition, the harmonin homology domain (HHD) (or harmonin-N-terminal domain) from whirlin ( 28 ), harmonin ( 29 ), cerebral cavernous malformation 2 (CCM2) ( 30 ), and regulator of telomere elongation helicase 1 (RTEL1) ( 31 ) was assigned to the αα-hub domain group ( 24 ) ( Figs. 1 E and 2 E ).…”

Section: The αα-Hubsmentioning

confidence: 99%

αα-Hub domains and intrinsically disordered proteins: A decisive combo

Bugge

Staby

Salladini

et al. 2021

Journal of Biological Chemistry

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Hub proteins are central nodes in protein–protein interaction networks with critical importance to all living organisms. Recently, a new group of folded hub domains, the αα-hubs, was defined based on a shared αα-hairpin supersecondary structural foundation. The members PAH, RST, TAFH, NCBD, and HHD are found in large proteins such as Sin3, RCD1, TAF4, CBP, and harmonin, which organize disordered transcriptional regulators and membrane scaffolds in interactomes of importance to human diseases and plant quality. In this review, studies of structures, functions, and complexes across the αα-hubs are described and compared to provide a unified description of the group. This analysis expands the associated molecular concepts of “one domain–one binding site”, motif-based ligand binding, and coupled folding and binding of intrinsically disordered ligands to additional concepts of importance to signal fidelity. These include context, motif reversibility, multivalency, complex heterogeneity, synergistic αα-hub:ligand folding, accessory binding sites, and supramodules. We propose that these multifaceted protein–protein interaction properties are made possible by the characteristics of the αα-hub fold, including supersite properties, dynamics, variable topologies, accessory helices, and malleability and abetted by adaptability of the disordered ligands. Critically, these features provide additional filters for specificity. With the presentations of new concepts, this review opens for new research questions addressing properties across the group, which are driven from concepts discovered in studies of the individual members. Combined, the members of the αα-hubs are ideal models for deconvoluting signal fidelity maintained by folded hubs and their interactions with intrinsically disordered ligands.

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Conformational switch of harmonin, a submembrane scaffold protein of the hair cell mechanoelectrical transduction machinery

Cited by 9 publications

References 42 publications

Phylogenetic analysis of Harmonin homology domains

Phylogenetic analysis of Harmonin homology domains

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

αα-Hub domains and intrinsically disordered proteins: A decisive combo

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