期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 28, 页码 9610-9615出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0803189105
关键词
Ca2+ release channels; cryo-EM; 3D structure; modeling
资金
- MRC [G0600084] Funding Source: UKRI
- Medical Research Council [G0600084] Funding Source: Medline
- NCRR NIH HHS [P41 RR002250-226483, P41 RR002250-237245, P41 RR002250, P41RR02250] Funding Source: Medline
- NEI NIH HHS [PN2 EY016525, PN2EY016525] Funding Source: Medline
- NIAMS NIH HHS [R01AR41802, R01 AR044864-10, R01 AR044864, R01AR44864, R01 AR041802, R01 AR041802-14] Funding Source: Medline
- NIGMS NIH HHS [R01 GM072804, P01GM064692, R01GM072804, P01 GM064692, P01GM99116, R01 GM080139-03, R01 GM080139-02, R01 GM080139] Funding Source: Medline
- Medical Research Council [G0600084] Funding Source: researchfish
The skeletal muscle Ca2+ release channel (RyR1), a homotetramer, regulates the release of Ca2+ from the sarcoplasmic reticulum to initiate muscle contraction. In this work, we have delineated the RyR1 monomer boundaries in a subnanometer-resolution electron cryomicroscopy (cryo-EM) density map. In the cytoplasmic region of each RyR1 monomer, 36 alpha-helices and 7 beta-sheets can be resolved. A beta-sheet was also identified close to the membrane-spanning region that resembles the cytoplasmic pore structures of inward rectifier K+ channels. Three structural folds, generated for amino acids 12-565 using comparative modeling and cryo-EM density fitting, localize close to regions implicated in communication with the voltage sensor in the transverse tubules. Eleven of the 15 disease-related residues for these domains are mapped to the surface of these models. Four disease-related residues are found in a basin at the interfaces of these regions, creating a pocket in which the immunophilin FKBP12 can fit. Taken together, these results provide a structural context for both channel gating and the consequences of certain malignant hyperthermia and central core disease-associated mutations in RyR1.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据