PDBsum entry: 3hsm

Signaling protein

PDB id: 3hsm

Contents

Protein chains

164 a.a. *

159 a.a. *

Waters ×39

* Residue conservation analysis

PDB id:

3hsm

Name:

Signaling protein

Title:

Crystal structure of distal n-terminal beta-trefoil domain of ryanodine receptor type 1

Structure:

Ryanodine receptor 1. Chain: a, b. Fragment: sequence database residues 1-210. Synonym: ryr-1, ryr1, skeletal muscle-type ryanodine receptor, skeletal muscle calcium release channel. Engineered: yes

Source:

Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Gene: ryr1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.50Å R-factor: 0.229 R-free: 0.276

Authors:

F.J.Amador,S.Liu,N.Ishiyama,M.J.Plevin,A.Wilson, D.H.Maclennan,M.Ikura

Key ref:

F.J.Amador et al. (2009). Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation "hot spot" loop. Proc Natl Acad Sci U S A, 106, 11040-11044. PubMed id: 19541610 DOI: 10.1073/pnas.0905186106

Date:

10-Jun-09 Release date: 28-Jul-09

Protein chain

P11716  (RYR1_RABIT) -  Ryanodine receptor 1

Seq: 5037 a.a.

Struc: 164 a.a.

Protein chain

P11716  (RYR1_RABIT) -  Ryanodine receptor 1

Seq: 5037 a.a.

Struc: 159 a.a.

 Gene Ontology (GO) functional annotation 

• Cellular component: membrane (1 term)

DOI no: 10.1073/pnas.0905186106

Proc Natl Acad Sci U S A 106:11040-11044 (2009)

PubMed id: 19541610

Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation "hot spot" loop.

F.J.Amador, S.Liu, N.Ishiyama, M.J.Plevin, A.Wilson, D.H.MacLennan, M.Ikura.

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.

Selected figure(s)

Figure 1.
Features of the RyR[NTD] structure. (A) Ribbon diagram of rabbit RyR[NTD]. The β-trefoil structure is separated into barrel (blue strands) and cap (green strands). Dotted lines represent missing residues. A top-down view is shown on the right side. (B) Sequence alignment of the distal N-terminal residues of RyR and IP[3]R isoforms. Residues highlighted in teal, yellow, and magenta denote conservation in the different layers of the barrel in both RyR[NTD] and IP[3]R[sup]. Residues in red text correspond to mutations sites in RyR1 that lead to MH or CCD, as well as to catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD2) for RyR2.

Figure 2.
Comparison of RyR[NTD] and IP[3]R[sup] structures. (A) Structural alignment of RyR[NTD] (purple) and IP[3]R[sup] (gray) structures. Topology diagram for both structures are shown in B. The 3-fold symmetry of the β-trefoil is evident, as well as differences in the arm domain. The layering of residues in the barrel is shown in C with the same color scheme as in Fig. 1B. Electrostatic surface representation is represented for IP[3]R[sup] and RyR[NTD] in D. A positive patch where mutations cluster is outlined in yellow. Residues with basic side groups found within and around the HS-loop are labeled. The structure is oriented in the top-down view described in Fig. 1A.

Figures were selected by an automated process.