Structures of the junctophilin/voltage-gated calcium channel interface reveal hot spot for cardiomyopathy mutations

SignificanceIon channels have evolved the ability to communicate with one another, either through protein-protein interactions, or indirectly via intermediate diffusible messenger molecules. In special cases, the channels are part of different membranes. In muscle tissue, the T-tubule membrane is in...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 119; no. 10; p. e2120416119
Main Authors Yang, Zheng Fang, Panwar, Pankaj, McFarlane, Ciaran R, Tuinte, Wietske E, Campiglio, Marta, Van Petegem, Filip
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 08.03.2022
Subjects
Arrhythmia
Binding sites
Biological Sciences
Calcium
Calcium channels
Calcium channels (L-type)
Calcium channels (voltage-gated)
Calcium Channels, L-Type - chemistry
Calcium Channels, L-Type - metabolism
Calcium-binding protein
Cardiac muscle
Cardiomyopathy
Cardiomyopathy, Hypertrophic - genetics
Clustering
Crystal structure
Crystallography, X-Ray
Humans
Huntington's disease
Huntingtons disease
Ion Channel Gating
Ion channels
Isoforms
Lipids
Membranes
Muscle contraction
Muscles
Mutation
Protein Conformation
Protein Isoforms - chemistry
Protein Isoforms - metabolism
Proteins
Sarcoplasmic reticulum
muscle excitation–contraction coupling
cardiomyopathy
calcium release
ion channels
calcium signaling
Online AccessGet full text

Cover

More Information
Summary:SignificanceIon channels have evolved the ability to communicate with one another, either through protein-protein interactions, or indirectly via intermediate diffusible messenger molecules. In special cases, the channels are part of different membranes. In muscle tissue, the T-tubule membrane is in proximity to the sarcoplasmic reticulum, allowing communication between L-type calcium channels and ryanodine receptors. This process is critical for excitation-contraction coupling and requires auxiliary proteins like junctophilin (JPH). JPHs are targets for disease-associated mutations, most notably hypertrophic cardiomyopathy mutations in the JPH2 isoform. Here we provide high-resolution snapshots of JPH, both alone and in complex with a calcium channel peptide, and show how this interaction is targeted by cardiomyopathy mutations.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
1Z.F.Y. and P.P. contributed equally to this work.
Edited by Kurt Beam, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO; received November 8, 2021; accepted January 31, 2022
Author contributions: Z.F.Y., P.P., W.E.T., M.C., and F.V.P. designed research; Z.F.Y., P.P., C.R.M., W.E.T., and M.C. performed research; Z.F.Y., P.P., C.R.M., W.E.T., M.C., and F.V.P. analyzed data; and Z.F.Y., W.E.T., M.C., and F.V.P. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2120416119