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TitleMolecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 2821, Year 2022
Publish dateMay 20, 2022
AuthorsTakuya Kobayashi / Akihisa Tsutsumi / Nagomi Kurebayashi / Kei Saito / Masami Kodama / Takashi Sakurai / Masahide Kikkawa / Takashi Murayama / Haruo Ogawa /
PubMed AbstractCardiac ryanodine receptor (RyR2) is a large Ca release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca and RyR2 ...Cardiac ryanodine receptor (RyR2) is a large Ca release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca and RyR2 mutations are implicated in severe arrhythmogenic diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remains unknown. Here, we address the gating mechanism of RyR2 by combining high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated two fundamental mechanisms for channel gating: interactions close to the channel pore stabilize the channel to prevent hyperactivity and a series of interactions in the surrounding regions is necessary for channel opening upon Ca binding. Mutations at the residues involved in the former and the latter mechanisms cause gain-of-function and loss-of-function, respectively. Our results reveal gating mechanisms of the RyR2 channel and alterations by pathogenic mutations at the atomic level.
External linksNat Commun / PubMed:35595836 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.72 Å
Structure data

EMDB-32036, PDB-7vmr:
Structure of recombinant RyR2 mutant K4593A (EGTA dataset)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-33935, PDB-7vml:
Structure of recombinant RyR2 (EGTA dataset, class 1&2, closed state)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-33936, PDB-7vmm:
Structure of recombinant RyR2 (EGTA dataset, class 1, closed state)
Method: EM (single particle) / Resolution: 3.49 Å

EMDB-33937, PDB-7vmn:
Structure of recombinant RyR2 (EGTA dataset, class 2, closed state)
Method: EM (single particle) / Resolution: 3.52 Å

EMDB-33938, PDB-7vmo:
Structure of recombinant RyR2 (Ca2+ dataset, class 1, open state)
Method: EM (single particle) / Resolution: 3.45 Å

EMDB-33939, PDB-7vmp:
Structure of recombinant RyR2 (Ca2+ dataset, class 2, open state)
Method: EM (single particle) / Resolution: 3.51 Å

EMDB-33940: Structure of recombinant RyR2 (Ca2+ dataset, class 3, open state)
Method: EM (single particle) / Resolution: 3.72 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / CALCIUM / CALCIUM CHANNEL / CALCIUM TRANSPORT / ION TRANSPORT / IONIC CHANNEL / METAL TRANSPORT / ER/SR MEMBRANE / RYANODINE RECEPTOR / RYANODINE / RECEPTOR / WILD TYPE

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