Publication Date:
2014-12-18
Description:
The ryanodine receptors (RyRs) are high-conductance intracellular Ca(2+) channels that play a pivotal role in the excitation-contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 A, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative-charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338550/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338550/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yan, Zhen -- Bai, Xiao-chen -- Yan, Chuangye -- Wu, Jianping -- Li, Zhangqiang -- Xie, Tian -- Peng, Wei -- Yin, Chang-cheng -- Li, Xueming -- Scheres, Sjors H W -- Shi, Yigong -- Yan, Nieng -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- England -- Nature. 2015 Jan 1;517(7532):50-5. doi: 10.1038/nature14063. Epub 2014 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [3] Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; 1] Ministry of Education Key Laboratory of Protein Science, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; 1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; Department of Biophysics, the Health Science Center &Center for Protein Science, Peking University, Beijing 100191, China. ; Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25517095" target="_blank"〉PubMed〈/a〉
Keywords:
Algorithms
;
Allosteric Regulation
;
Animals
;
Cryoelectron Microscopy
;
Ion Channel Gating
;
Models, Molecular
;
Molecular Weight
;
Protein Multimerization
;
Protein Structure, Tertiary
;
Rabbits
;
Ryanodine Receptor Calcium Release Channel/*chemistry/metabolism/*ultrastructure
;
Sarcoplasmic Reticulum/chemistry
;
Tacrolimus Binding Protein 1A/chemistry/metabolism/ultrastructure
;
Zinc Fingers
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
