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Structures and allosteric motions of Ryanodine Receptor Domains
Author(s) -
Van Petegem Filip,
Tung ChingChieh,
Kimlicka Lynn,
Yuchi Michael,
Lobo Paolo A,
Lau Kelvin
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.590.6
Subject(s) - ryanodine receptor , allosteric regulation , endoplasmic reticulum , gating , biophysics , mutant , chemistry , mutation , ion channel , skeletal muscle , microbiology and biotechnology , receptor , biology , biochemistry , gene , anatomy
Ryanodine Receptors (RyRs) form large (>;2.2 MDa) ion channels that release Ca2+ from the endoplasmic and sarcoplasmic reticulum. They are thus involved in many calcium‐dependent events, including the contraction of skeletal and cardiac muscle. Mutation in the ryr genes can cause severe skeletal muscle disorders and cardiac arrhythmias. Here we present our recent insights in the structure‐function of these membrane protein giants. We have solved crystal structures of multiple domains in the N‐terminal and central regions and mapped the positions of ~100 disease‐causing mutations. By creating pseudo‐atomic models, we analyzed the motions these domains undergo during opening and closing of the pore region. Channel opening includes major motions in the central rim. Incidentally, this area contains a hot spot for disease mutations (>;80 total). In particular, channel opening disrupts an intersubunit interface that contains the largest cluster of mutations. By solving structures of several mutant forms of the domains, we observe that mutations can alter relative domain orientations. They thus mimic the effect of binding of ligands to the related IP3 receptor. Overall, we present a model whereby the N‐terminal region of the RyR serves as a gating ring that forms a hub for allosteric control.