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PMID: 25470061 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Structure of a mammalian ryanodine receptor.

Nature ·Vol. 517 ·No. 7532 ·2015-01-01 ·Pages 44-9

Zalk R, Clarke OB, des Georges A, Grassucci RA, Reiken S, Mancia F, Hendrickson WA, Frank J, Marks AR

Abstract

Ryanodine receptors (RyRs) mediate the rapid release of calcium (Ca(2+)) from intracellular stores into the cytosol, which is essential for numerous cellular functions including excitation-contraction coupling in muscle. Lack of sufficient structural detail has impeded understanding of RyR gating and regulation. Here we report the closed-state structure of the 2.3-megadalton complex of the rabbit skeletal muscle type 1 RyR (RyR1), solved by single-particle electron cryomicroscopy at an overall resolution of 4.8 Å. We fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in unprecedented detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture places it in the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca(2+).

MeSH Terms
Animals Calcium/deficiency,metabolism,pharmacology Cell Membrane/metabolism Cryoelectron Microscopy Cytosol/metabolism Ion Channel Gating/drug effects Muscle, Skeletal/chemistry Protein Structure, Tertiary Rabbits Ryanodine Receptor Calcium Release Channel/chemistry,metabolism,ultrastructure Tacrolimus Binding Proteins/chemistry,metabolism
Chemicals
Ryanodine Receptor Calcium Release Channel Tacrolimus Binding Proteins Calcium
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Zalk Ran
Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
Clarke Oliver B
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
des Georges Amédée
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Grassucci Robert A
1] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA [2] Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA.
Reiken Steven
Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
Mancia Filippo
Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
Hendrickson Wayne A
1] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [2] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Frank Joachim
1] Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA [2] Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA [3] Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
Marks Andrew R
1] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [2] Department of Medicine, Columbia University, New York, New York 10032, USA [3] Wu Center for Molecular Cardiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature13950
Published
2015-01-01
Epub
2014-00-01
Pages
44-9
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4300236
Subset
IM
Grants
NHLBI NIH HHS · R01 HL061503 · United States
NIGMS NIH HHS · R01 GM029169 · United States
NIGMS NIH HHS · R01GM29169 · United States
NIAMS NIH HHS · R01 AR060037 · United States
NIGMS NIH HHS · U54 GM095315 · United States
NHLBI NIH HHS · P01 HL081172 · United States
NIAMS NIH HHS · R01AR060037 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · U54GM095315 · United States
NHLBI NIH HHS · R01 HL083418 · United States
NHLBI NIH HHS · R01HL061503 · United States
Databases
PDB
3J8E
External Links
PubMed source DOI: 10.1038/nature13950 PMC Full Text View journal details
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