Abstract
Ryanodine receptors (RyRs) are ion channels that regulate muscle contraction by releasing calcium ions from intracellular stores into the cytoplasm. Mutations in skeletal muscle RyR (RyR1) give rise to congenital diseases such as central core disease. The absence of high-resolution structures of RyR1 has limited our understanding of channel function and disease mechanisms at the molecular level. Here, we report a structural model of the pore-forming region of RyR1. Molecular dynamics simulations show high ion binding to putative pore residues D4899, E4900, D4938, and D4945, which are experimentally known to be critical for channel conductance and selectivity. We also observe preferential localization of Ca2+ over K+ in the selectivity filter of RyR1. Simulations of RyR1-D4899Q mutant show a loss of preference to Ca2+ in the selectivity filter as seen experimentally. Electrophysiological experiments on a central core disease mutant, RyR1-G4898R, show constitutively open channels that conduct K+ but not Ca2+. Our simulations with G4898R likewise show a decrease in the preference of Ca2+ over K+ in the selectivity filter. Together, the computational and experimental results shed light on ion conductance and selectivity of RyR1 at an atomistic level.
Highlights
Muscle contraction upon excitation by nerve impulse is initiated by a rapid rise in cytoplasmic Ca2+
Congenital mutations in a specific type of Ryanodine receptors (RyRs) that is present in skeletal muscles, RyR1, lead to central core disease (CCD), which leads to weakened muscle
It is generally known that CCD mutations abort RyR1 function, the molecular basis of RyR1 dysfunction remains largely unknown because of the lack of atomic-level structure
Summary
Muscle contraction upon excitation by nerve impulse is initiated by a rapid rise in cytoplasmic Ca2+. RyRs are large tetrameric ion channels (molecular weight of 2.26 MDa) present in the membranes of endoplasmic/sarcoplasmic reticulum. They have high conductance for monovalent (,800 pS with 250 mM K+ as conducting ion) and divalent cations (,150 pS with 50 mM Ca2+), while being selective for divalent cations (PCa/PK,7) [3]. RyRs are important mediators of excitation-contraction coupling and congenital mutations of RyRs result in neuromuscular diseases such as malignant hypothermia and central core disease (CCD) [4]. Mutations result in non-functional channels [4] leading to CCD. A structural model of the pore region that would reveal the location and function of these residues will be useful in understanding the role of these residues in channel function
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