Structures of the junctophilin/voltage-gated calcium channel interface reveal hot spot for cardiomyopathy mutations
Junctophilins (JPH) are a class of proteins found at junctions between the plasma membrane and the endoplasmic or sarcoplasmic reticulum, allowing for communications between proteins embedded in different membranes. JPHs have been proposed to interact with lipids as well as several ion channels, all...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2022-03, Vol.119 (10), p.1-10 |
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| creator | Panwar, Pankaj McFarlane, Ciaran R. Tuinte, Wietske E. Campiglio, Marta Van Petegem, Filip |
| description | Junctophilins (JPH) are a class of proteins found at junctions between the plasma membrane and the endoplasmic or sarcoplasmic reticulum, allowing for communications between proteins embedded in different membranes. JPHs have been proposed to interact with lipids as well as several ion channels, allowing for specialized communication between them. The JPH3 isoform is the target for repeats that cause Huntington’s disease-like 2, whereas JPH2 is a hot spot for mutations linked to cardiomyopathy. Here we present crystal structures of two JPH isoforms, which resemble a twisted skeleton with ribs formed by membrane occupation recognition nexus repeats, and a backbone built by a long α-helix. We captured the structure of a complex between JPH2 and a C-terminal binding site in the L-type calcium channel (CaV1.1) and show that this interaction is required for clustering of these channels and for robust muscle excitation–contraction coupling. Over 80 sequence variants linked to cardiomyopathy are found in different structurally important regions of JPH2, most of which affect stabilizing interactions. A subset directly affects the interaction with the L-type calcium channel. In parallel, sequence variants in the L-type calcium channel, linked to cardiac arrhythmia, also affect critical interactions. |
| doi_str_mv | 10.1073/pnas.2120416119 |
| format | Article |
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JPHs have been proposed to interact with lipids as well as several ion channels, allowing for specialized communication between them. The JPH3 isoform is the target for repeats that cause Huntington’s disease-like 2, whereas JPH2 is a hot spot for mutations linked to cardiomyopathy. Here we present crystal structures of two JPH isoforms, which resemble a twisted skeleton with ribs formed by membrane occupation recognition nexus repeats, and a backbone built by a long α-helix. We captured the structure of a complex between JPH2 and a C-terminal binding site in the L-type calcium channel (CaV1.1) and show that this interaction is required for clustering of these channels and for robust muscle excitation–contraction coupling. Over 80 sequence variants linked to cardiomyopathy are found in different structurally important regions of JPH2, most of which affect stabilizing interactions. A subset directly affects the interaction with the L-type calcium channel. In parallel, sequence variants in the L-type calcium channel, linked to cardiac arrhythmia, also affect critical interactions.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2120416119</identifier><identifier>PMID: 35238659</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>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</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-03, Vol.119 (10), p.1-10</ispartof><rights>Copyright National Academy of Sciences Mar 8, 2022</rights><rights>Copyright © 2022 the Author(s). 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JPHs have been proposed to interact with lipids as well as several ion channels, allowing for specialized communication between them. The JPH3 isoform is the target for repeats that cause Huntington’s disease-like 2, whereas JPH2 is a hot spot for mutations linked to cardiomyopathy. Here we present crystal structures of two JPH isoforms, which resemble a twisted skeleton with ribs formed by membrane occupation recognition nexus repeats, and a backbone built by a long α-helix. We captured the structure of a complex between JPH2 and a C-terminal binding site in the L-type calcium channel (CaV1.1) and show that this interaction is required for clustering of these channels and for robust muscle excitation–contraction coupling. Over 80 sequence variants linked to cardiomyopathy are found in different structurally important regions of JPH2, most of which affect stabilizing interactions. A subset directly affects the interaction with the L-type calcium channel. 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| 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 |
| title | Structures of the junctophilin/voltage-gated calcium channel interface reveal hot spot for cardiomyopathy mutations |
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