8Z3F

Complex structure of CIB2 and TMC1 CR1

8Z3F の概要

• エントリーDOI: 10.2210/pdb8z3f/pdb
• 分子名称: Calcium and integrin-binding family member 2, Transmembrane channel-like protein 1, CALCIUM ION, ... (4 entities in total)
• 機能のキーワード: calcium binding, metal binding protein
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28271.41

構造登録者

Wu, S.,Lin, L.,Lu, Q. (登録日: 2024-04-15, 公開日: 2025-02-19, 最終更新日: 2025-06-25)

主引用文献

Wu, S.,Lin, L.,Hu, Q.,Yao, X.,Wang, H.,Liu, S.,Liu, Q.,Xi, Y.,Lin, Y.,Gong, J.,Hu, R.,Zhan, W.,Luo, Y.,He, G.,Liu, Z.,Xiong, W.,Wang, Q.,Xu, Z.,Bai, F.,Lu, Q.
Mechano-electrical transduction components TMC1-CIB2 undergo a Ca 2+ -induced conformational change linked to hearing loss.
Dev.Cell, 60:1586-, 2025

PubMed Abstract: TMC1, a unique causative gene associated with deafness, exhibits variants with autosomal dominant and recessive inheritance patterns. TMC1 codes for the transmembrane channel-like protein 1 (TMC1), a key component of the mechano-electrical transduction (MET) machinery for hearing. However, the molecular mechanism of Ca regulation in MET remains unclear. Calcium and integrin-binding protein 2 (CIB2), another MET component associated with deafness, can bind with Ca. Our study shows that TMC1-CIB2 complex undergoes a Ca-induced conformational change. We identified a vertebrate-specific binding site on TMC1 that interacts with apo CIB2, linked with hearing loss. Using an ex vivo mouse organotypic cochlea model, we demonstrated that disruption of the calcium-binding site of CIB2 perturbs the MET channel conductivity. After systematically analyzing the hearing loss variants, we observed dominant mutations of TMC1 cluster around the putative ion pore or at the binding interfaces with CIB2. These findings elucidate the molecular mechanisms underlying TMC1-linked hearing loss.

PubMed: 39889697
DOI: 10.1016/j.devcel.2025.01.004

実験手法

X-RAY DIFFRACTION (1.74 Å)