The human ryanodine receptor 2 (hRyR2), the largest ion channel so far known, mediates calcium release from the sarcoplasmic reticulum into the cytoplasm of cardiac myocytes. It is a transmembrane protein composed of four identical subunits (each of approximately 5000 amino acids), each of which contains 14 domains [1]. hRyR2 is predominantly expressed in heart tissue and is a principal component of cardiac excitation-contraction coupling, which enables regular heart contraction. Several mutations in the gene of this protein are associated with severe cardiac arrhythmias (catecholaminergic polymorphic ventricular tachycardia, CPVT1 and arrhytmogenic right ventricular dysplasia, ARVD2), often causing human death. Here we present a detailed analysis of the N-terminal part of hRyR2 using a 2.38 Å crystal structure (residues 1–606), encompassing ≈ 33 mutations which have been linked to these diseases [2]. This part consists of three domains (INS, MIR, RIH) which are held together by a unique interaction network, in which a key role is played by the central helix (the helix preceding the RIH domain). Interestingly, a chloride binding site, reported to be crucial for the stability of the N-terminal region of mouse RyR2 [3], was not observed. The tertiary structure of this fragment also allows us to better understand the physical mechanisms by which several mutations within hRyR2 cause CPVT1 and ARVD2. Finally, we used this structure to help locate the positon of the N-terminal region within the whole ryanodine receptor using previously published electron microscopy data [4].
This work was supported by research grants from the Slovak Grant Agency (VEGA No. 2/0131/10 and 2/0148/14), the Slovak Research and Development Agency (APVV0628-10 and APVV-0721-10) and the British Heart Foundation. The attendance of VBH at the XIII Discussions in Structural Molecular Biology was funded by MVTS 1520.