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

Borko, L., Bauerova-Hlinkova, V., Hostinova, E., Gasperik, J., Beck, K. ORCID: https://orcid.org/0000-0001-5098-9484, Lai, F. A. ORCID: https://orcid.org/0000-0003-2852-8547, Zahradnikova, A. and Sevcik, J. 2014. Structural insights into the human RyR2 N-terminal region involved in cardiac arrhythmias. Acta Crystallographica Section D: Structural Biology 70 (11) , pp. 2897-2912. 10.1107/S1399004714020343

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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:	Published Online
Status:	Published
Schools:	Dentistry Biosciences
Publisher:	International Union of Crystallography
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	10 September 2014
Last Modified:	05 Jan 2024 08:14
URI:	https://orca.cardiff.ac.uk/id/eprint/68576

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