PDBsum entry 3im5

Signaling protein

PDB id: 3im5

Contents

Protein chains

173 a.a. *

176 a.a. *

Waters ×34

* Residue conservation analysis

PDB id:

3im5

Name:

Signaling protein

Title:

Crystal structure of mouse ryanodine receptor 2 (residues 1-217)

Structure:

Cardiac ca2+ release channel. Chain: a, b. Fragment: n-terminal domain. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: ryr2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.55Å R-factor: 0.225 R-free: 0.288

Authors:

F.Van Petegem,P.A.Lobo

Key ref:

P.A.Lobo and F.Van Petegem (2009). Crystal structures of the N-terminal domains of cardiac and skeletal muscle ryanodine receptors: insights into disease mutations. Structure, 17, 1505-1514. PubMed id: 19913485 DOI: 10.1016/j.str.2009.08.016

Date:

09-Aug-09 Release date: 17-Nov-09

Protein chain

E9Q401  (RYR2_MOUSE) -  Ryanodine receptor 2 from Mus musculus

Seq: 4966 a.a.

Struc: 173 a.a.

Protein chain

E9Q401  (RYR2_MOUSE) -  Ryanodine receptor 2 from Mus musculus

Seq: 4966 a.a.

Struc: 176 a.a.

DOI no: 10.1016/j.str.2009.08.016

Structure 17:1505-1514 (2009)

PubMed id: 19913485

Crystal structures of the N-terminal domains of cardiac and skeletal muscle ryanodine receptors: insights into disease mutations.

P.A.Lobo, F.Van Petegem.

ABSTRACT

Ryanodine receptors (RyRs) are channels governing the release of Ca(2+) from the sarcoplasmic or endoplasmic reticulum. They are required for the contraction of both skeletal (RyR1) and cardiac (RyR2) muscles. Mutations in both RyR1 and RyR2 have been associated with severe genetic disorders, but high-resolution data describing the disease variants in detail have been lacking. Here we present the crystal structures of the N-terminal domains of both RyR2 (1-217) and RyR1 (9-205) at 2.55 A and 2.9 A, respectively. The domains map in a hot spot region for disease mutations. Both structures consist of a core beta trefoil domain flanked by an alpha helix. Crystal structures of two RyR2 disease mutants, A77V (2.2 A) and V186M (1.7 A), show that the mutations cause distinct local changes in the surface of the protein. A RyR2 deletion mutant causes significant changes in the thermal stability. The disease positions highlight two putative binding interfaces required for normal RyR function.

Selected figure(s)

Figure 1.
Figure 1. Overall Structure of the RyR NTD
(A) Overall fold of the RyR2 NTD, showing the α helix (α1) and 3[10] helix (3[10]h1) in red, β strands in blue, and loops in white. Two views are shown (labeled “front” and “back”), rotated 180° around a vertical axis. All β strands are labeled for reference. Loops present in the construct but not modeled are shown as dotted lines. W98 in the α1-β5 loop is shown in stick representation. The positions of the amino- and carboxytermini are indicated.
(B) Sequence alignment of the NTD of mouse RyR2, rabbit RyR1, and human RyR3. Conserved residues are highlighted in gray. Secondary structure elements are shown on top (RyR2) and at the bottom (RyR1). Sequence stretches present in the constructs but not modeled in the electron density are shown as dotted lines. Positions found in disease mutations are marked with an asterisk and highlighted in red.
(C) Superposition of the backbone trace of RyR1 (green) and RyR2 NTD (blue). Loops with conformational changes are highlighted. The view is the same as the front view of Figure 1A.

Figure 3.
Figure 3. RyR2 A77V and V186M Mutations Cause Distinct Changes in the Surface
(A) Superposition of RyR2 wild-type (blue) and RyR2 A77V (orange) in the region surrounding the mutation. Nitrogen atoms are shown as dark blue, oxygen in red, and sulfur in yellow. The inset shows the view (box) relative to the full domain.
(B) Superposition of RyR2 wild-type (blue) with RyR2 V186M (brown).
(C and D) Surface representation of RyR2 wild-type (blue) with the surface of the superposed A77V and V186M mutations shown as a mesh. The views are identical to the ones for the corresponding Figures 3A and 3B. The A77V and V186M mutations alter the local surface. Numbers shown are solvent accessible areas, with the first number for the wild-type residue, and the second for the mutant.

The above figures are reprinted by permission from Cell Press: Structure (2009, 17, 1505-1514) copyright 2009.

Figures were selected by the author.