4I8M

Crystal structure of rabbit Ryanodine receptor 1 (residues 1-536) disease mutant V219I

Summary for 4I8M

• Entry DOI: 10.2210/pdb4i8m/pdb
• Related: 2XOA 4I0Y 4I1E 4I2S 4I37 4I3N 4I6I 4I7I 4I96
• Descriptor: Ryanodine receptor 1, GLYCEROL (3 entities in total)
• Functional Keywords: calcium channel, sr/er membrane, metal transport
• Biological source: Oryctolagus cuniculus (rabbit)
• Cellular location: Sarcoplasmic reticulum membrane; Multi-pass membrane protein: P11716
• Total number of polymer chains: 1
• Total formula weight: 59582.50

Authors

Kimlicka, L.,Van Petegem, F. (deposition date: 2012-12-03, release date: 2013-02-20, Last modification date: 2023-09-20)

Primary citation

Kimlicka, L.,Lau, K.,Tung, C.C.,Van Petegem, F.
Disease mutations in the ryanodine receptor N-terminal region couple to a mobile intersubunit interface.
Nat Commun, 4:1506-1506, 2013

PubMed Abstract: Ryanodine receptors are large channels that release Ca(2+) from the endoplasmic and sarcoplasmic reticulum. Hundreds of RyR mutations can cause cardiac and skeletal muscle disorders, yet detailed mechanisms explaining their effects have been lacking. Here we compare pseudo-atomic models and propose that channel opening coincides with widening of a cytoplasmic vestibule formed by the N-terminal region, thus altering an interface targeted by 20 disease mutations. We solve crystal structures of several disease mutants that affect intrasubunit domain-domain interfaces. Mutations affecting intrasubunit ionic pairs alter relative domain orientations, and thus couple to surrounding interfaces. Buried disease mutations cause structural changes that also connect to the intersubunit contact area. These results suggest that the intersubunit contact region between N-terminal domains is a prime target for disease mutations, direct or indirect, and we present a model whereby ryanodine receptors and inositol-1,4,5-trisphosphate receptors are activated by altering domain arrangements in the N-terminal region.

PubMed: 23422674
DOI: 10.1038/ncomms2501

Experimental method

X-RAY DIFFRACTION (2.8 Å)