3HSM

Crystal structure of distal N-terminal beta-trefoil domain of Ryanodine Receptor type 1

Summary for 3HSM

• Entry DOI: 10.2210/pdb3hsm/pdb
• Descriptor: Ryanodine receptor 1 (2 entities in total)
• Functional Keywords: beta-trefoil, calcium, calcium channel, calcium transport, glycoprotein, ion transport, ionic channel, membrane, phosphoprotein, receptor, s-nitrosylation, transmembrane, transport, signaling protein
• Biological source: Oryctolagus cuniculus (rabbit)
• Cellular location: Sarcoplasmic reticulum membrane ; Multi-pass membrane protein : P11716
• Total number of polymer chains: 2
• Total formula weight: 46550.46

Authors

Amador, F.J.,Liu, S.,Ishiyama, N.,Plevin, M.J.,Wilson, A.,MacLennan, D.H.,Ikura, M. (deposition date: 2009-06-10, release date: 2009-07-28, Last modification date: 2023-09-06)

Primary citation

Amador, F.J.,Liu, S.,Ishiyama, N.,Plevin, M.J.,Wilson, A.,MacLennan, D.H.,Ikura, M.
Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation "hot spot" loop
Proc.Natl.Acad.Sci.USA, 106:11040-11044, 2009

PubMed Abstract: Muscle contraction and relaxation is regulated by transient elevations of myoplasmic Ca(2+). Ca(2+) is released from stores in the lumen of the sarco(endo)plasmic reticulum (SER) to initiate formation of the Ca(2+) transient by activation of a class of Ca(2+) release channels referred to as ryanodine receptors (RyRs) and is pumped back into the SER lumen by Ca(2+)-ATPases (SERCAs) to terminate the Ca(2+) transient. Mutations in the type 1 ryanodine receptor gene, RYR1, are associated with 2 skeletal muscle disorders, malignant hyperthermia (MH), and central core disease (CCD). The evaluation of proposed mechanisms by which RyR1 mutations cause MH and CCD is hindered by the lack of high-resolution structural information. Here, we report the crystal structure of the N-terminal 210 residues of RyR1 (RyR(NTD)) at 2.5 A. The RyR(NTD) structure is similar to that of the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor (IP(3)Rsup), but lacks most of the long helix-turn-helix segment of the "arm" domain in IP(3)Rsup. The N-terminal beta-trefoil fold, found in both RyR and IP(3)R, is likely to play a critical role in regulatory mechanisms in this channel family. A disease-associated mutation "hot spot" loop was identified between strands 8 and 9 in a highly basic region of RyR1. Biophysical studies showed that 3 MH-associated mutations (C36R, R164C, and R178C) do not adversely affect the global stability or fold of RyR(NTD), supporting previously described mechanisms whereby mutations perturb protein-protein interactions.

PubMed: 19541610
DOI: 10.1073/pnas.0905186106

Experimental method

X-RAY DIFFRACTION (2.5 Å)