Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Borko, Lubomir, Bauerova-Hlinkova, Vladena, Hostinova, Eva, Gasperik, Juraj, Beck, Konrad, Lai, Francis Anthony, Zahradnikova, Alexandra and Sevcik, Jozef 2014. Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias. Acta Crystallographica Section D: Biological Crystallography 70 (11) , pp. 2897-2912. 10.1107/S1399004714020343

[img]
Preview
PDF - Published Version
Download (3MB) | Preview
[img]
Preview
PDF - Supplemental Material
Download (923kB) | Preview

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 atom movements of up to 8 A ° 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Dentistry
Additional Information: Pdf uploaded in accordance with publisher's policies at http://www.sherpa.ac.uk/romeo/issn/0907-4449/ (accessed 19.11.14).
Publisher: International Union of Crystallography
ISSN: 0907-4449
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 10 September 2014
Last Modified: 28 Feb 2019 16:41
URI: http://orca.cf.ac.uk/id/eprint/68576

Citation Data

Cited 14 times in Google Scholar. View in Google Scholar

Cited 12 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics