한빛사논문
- 조회349
Do Hoon Kwon1,5, Feng Zhang1,5, Brett A. McCray2, Shasha Feng3, Meha Kumar2, Jeremy M. Sullivan2, Wonpil Im3, Charlotte J. Sumner2,4 & Seok-Yong Lee1
1Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
2Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3Departments of Biological Sciences, Chemistry, and Bioengineering, Lehigh University, Bethlehem, PA 18015, USA.
4Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
5These authors contributed equally: Do Hoon Kwon, Feng Zhang.
Corresponding author : Correspondence to Seok-Yong Lee.
Abstract
Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development.
논문정보
- Research article
- 2023년 06월 (BRIC 등록일 2023-06-27)
- 국외 연구진
- 생명과학 > 생화학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
