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Title: Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias

X-ray and solution structures of the human RyR2 N-terminal region were obtained under near-physiological conditions. The structure exhibits a unique network of interactions between its three domains, revealing an important stabilizing role of the central helix. 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 tomore » 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{sup 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.« less
Authors:
; ; ;  [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [1]
  1. Institute of Molecular Biology, Slovak Academy of Sciences, Dúbravská cesta 21, 845 51 Bratislava (Slovakia)
  2. Cardiff University School of Dentistry, Heath Park, Cardiff CF14 4XY Wales (United Kingdom)
  3. Cardiff University School of Medicine, Cardiff CF14 4XN Wales (United Kingdom)
  4. (Slovakia)
Publication Date:
OSTI Identifier:
22347726
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 70; Journal Issue: Pt 11; Other Information: PMCID: PMC4220973; PMID: 25372681; PUBLISHER-ID: lv5073; OAI: oai:pubmedcentral.nih.gov:4220973; Copyright (c) Borko et al. 2014; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; ATOMS; CALCIUM; CONTRACTION; CRYSTAL STRUCTURE; CRYSTALS; ELECTRON MICROSCOPY; ELECTRONS; INTERACTIONS; MATHEMATICAL SOLUTIONS; RECEPTORS; SOLUTIONS; SPIN; STABILITY; SURFACES