Deciphering the Molecular Interaction Between the Adhesion G Protein-Coupled Receptor ADGRV1 and its PDZ-Containing Regulator PDZD7

Abstract

Hearing relies on the transduction of sound-evoked vibrations into electrical signals, occurring in the stereocilia bundle of inner ear hair cells. The G protein-coupled receptor (GPCR) ADGRV1 and the multi-PDZ protein PDZD7 play a critical role in the formation and function of stereocilia through their scaffolding and signaling properties. During hair cell development, the GPCR activity of ADGRV1 is specifically inhibited by PDZD7 through an unknown mechanism. Here, we describe the key interactions mediated by the two N-terminal PDZ domains of PDZD7 and the cytoplasmic domain of ADGRV1. Both PDZ domains can bind to the C-terminal PDZ binding motif (PBM) of ADGRV1 with the critical contribution of atypical C-terminal β extensions. The two PDZ domains form a supramodule in solution, stabilized upon PBM binding. Interestingly, we showed that the stability and binding properties of the PDZ tandem are affected by two deafness-causing mutations located in the binding grooves of PDZD7 PDZ domains.

Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation

“…2c ). Weak association between ADGRV1 and PDZD7 was reported by using different assay methods 30 . However, ADGRV1-CT displayed no detectable interaction with PDZ12 or PDZ3 of PDZD7 in ITC-based assays (Fig.…”

Liquid-liquid phase separation in hair cell stereocilia development and maintenance

“…The adhesion molecule Usherin interacts with Adgrv1 to form the ankle link. Their CTs contain a PBM (PDZ binding motif), which can bind to the PDZ domain-containing protein Whirlin and PDZD7 (PDZ domain-containing protein 7, encoded by PDZD7, a modifier of Usher syndrome) [85] , [86] . Clarin-1 (encoded by USH3A) is the only known USH3 protein.…”

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss

“…In the inner ear, VLGR1 is expressed in the ankle region of HCs stereocilia, which can form the ankle-link complex with Usherin, Vezatin, and Whirlin ( Michalski et al, 2007 ). VLGR1 was identified to form a complex with Clarin-1, CDH23, and PCDH15 at the ribbon synapses of HCs ( Zallocchi et al, 2012b ), and can also interact with various proteins including Harmony ( Verpy et al, 2000 ), PDZ7 ( Colcombet-Cazenave et al, 2022 ), MyosinVIIa ( Michalski et al, 2007 ), and SNAP25 ( Zallocchi et al, 2012a ). In various VLGR1 mutant or knockout mouse models, the stereociliary development of auditory HCs is impaired, the ankle-links are absent, and hearing impairment of varying degrees occurs ( Skradski et al, 2001 ; McMillan and White, 2004 ; Yagi et al, 2005 ).…”