4JKQ

Crystal structure of the N-terminal region of the human ryanodine receptor 2

Summary for 4JKQ

• Entry DOI: 10.2210/pdb4jkq/pdb
• Related: 2XOA 3ILA 3IM5 3IM6 3IM7 4I0Y 4I1E 4I3N 4I6I 4I7I
• Descriptor: Ryanodine receptor 2 (2 entities in total)
• Functional Keywords: beta trefoil fold, unknown function
• Biological source: Homo sapiens (human)
• Cellular location: Sarcoplasmic reticulum membrane ; Multi-pass membrane protein : Q92736
• Total number of polymer chains: 1
• Total formula weight: 67916.98

Authors

Bauerova, V.,Sevcik, J. (deposition date: 2013-03-11, release date: 2014-04-02, Last modification date: 2023-09-20)

Primary citation

Borko, L.,Bauerova-Hlinkova, V.,Hostinova, E.,Gasperik, J.,Beck, K.,Lai, F.A.,Zahradnikova, A.,Sevcik, J.
Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias.
Acta Crystallogr.,Sect.D, 70:2897-2912, 2014

PubMed Abstract: Human ryanodine receptor 2 (hRyR2) mediates calcium release from the sarcoplasmic reticulum, enabling cardiomyocyte contraction. The N-terminal region of hRyR2 (amino acids 1-606) is the target of >30 arrhythmogenic mutations and contains a binding site for phosphoprotein phosphatase 1. Here, the solution and crystal structures determined under near-physiological conditions, as well as a homology model of the hRyR2 N-terminal region, are presented. The N-terminus is held together by a unique network of interactions among its three domains, A, B and C, in which the central helix (amino acids 410-437) plays a prominent stabilizing role. Importantly, the anion-binding site reported for the mouse RyR2 N-terminal region is notably absent from the human RyR2. The structure concurs with the differential stability of arrhythmogenic mutations in the central helix (R420W, I419F and I419F/R420W) which are owing to disparities in the propensity of mutated residues to form energetically favourable or unfavourable contacts. In solution, the N-terminus adopts a globular shape with a prominent tail that is likely to involve residues 545-606, which are unresolved in the crystal structure. Docking the N-terminal domains into cryo-electron microscopy maps of the closed and open RyR1 conformations reveals C(α) atom movements of up to 8 Å upon channel gating, and predicts the location of the leucine-isoleucine zipper segment and the interaction site for spinophilin and phosphoprotein phosphatase 1 on the RyR surface.

PubMed: 25372681
DOI: 10.1107/S1399004714020343

Experimental method

X-RAY DIFFRACTION (2.39 Å)