| Popis: |
Cardiac and skeletal muscles have different mechanisms of excitation-contraction coupling that depend on a set of tissue-specific protein isoforms. In heart, ryanodine receptor isoform 2 (RyR2), cardiac dihydropyridine receptor (DHPR) and FKBP12.6 together with other proteins couple the plasmalemmal depolarization to the release of Ca2+ from the sarcoplasmic reticulum (SR), via a calcium-induced calcium release mechanism. In skeletal muscle, RyR1, skeletal DHPR and FKBP12 together with other proteins couple these two events via an entirely different mechanism that requires a more direct RyR-DHPR coupling, and different long-range allosterism pathways.While the 3D structure of RyR1 has been solved at near-atomic resolution, the 3D structure of RyR2 lags significantly in resolution (currently ∼30 A). To start uncovering the different molecular mechanisms of these two main RyR isoforms, we have determined the 3D structure of RyR2 in complex with FKBP12.6 in the closed state at nanometer resolution. This has enabled building a pseudo-atomic model for RyR2. Comparative analysis between the RyR2 and RyR1 isoforms shows significant structural differences localized to specific domains, but not all structural differences can be explained by primary sequence divergence. These differences are interpreted in the context of the two modes of excitation-contraction coupling. The analysis of heterogeneity in the dataset allowed us to further define two conformations representing two functional states of RyR2.This work was supported by American Heart Association grant No. 14GRNT19660003 and Muscular Dystrophy Association grant No. MDA352845 (to MS). |
