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A Structural Model of the Pore-Forming Region of the Skeletal Muscle Ryanodine Receptor (RyR1)

By Srinivas Ramachandran, Adrian W. R. Serohijos, Le Xu, Gerhard Meissner and Nikolay V. Dokholyan

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:2668181
Provided by: PubMed Central
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    Citations

    1. (2005). (De)constructing the ryanodine receptor: modeling ion permeation and selectivity of the calcium release channel.
    2. (1992). A model for ionic conduction in the ryanodine receptor channel of sheep cardiac muscle sarcoplasmic reticulum.
    3. (2004). A model of the putative pore region of the cardiac ryanodine receptor channel 1.
    4. (1995). A smooth particle mesh Ewald method.
    5. (2002). Apocalmodulin and Ca 2+-calmodulin bind to neighboring locations on the ryanodine receptor.
    6. (1995). Association of triadin with the ryanodine receptor and calsequestrin in the lumen of the sarcoplasmic reticulum.
    7. (2000). Binding and selectivity in L-type calcium channels: a mean spherical approximation.
    8. (2001). Bridging the information gap: computational tools for intermediate resolution structure interpretation.
    9. (2003). Coat protein fold and maturation transition of bacteriophage P22 seen at subnanometer resolutions.
    10. (2007). Combined effect of pore radius and protein dielectric coefficient on the selectivity of a calcium channel.
    11. (1994). Cryo-electron microscopy and three-dimensional reconstruction of the calcium release channel/ryanodine receptor from skeletal muscle.
    12. (2002). Crystal structure and mechanism of a calcium-gated potassium channel.
    13. (2009). DirksenRT,AvilaG(2002)Alteredryanodinereceptorfunctionincentralcoredisease: leaky or uncoupled Ca 2+ release channels? Trends Cardiovasc Med 12: 189–197. RyR Pore Structure and Function PLoS
    14. (1998). Discrete molecular dynamics studies of the folding of a protein-like model.
    15. (1995). Electron cryomicroscopy and angular reconstitution used to visualize the skeletal muscle calcium release channel.
    16. (2001). Electron cryomicroscopy and bioinformatics suggest protein fold models for rice dwarf virus.
    17. (2006). Emergence of protein fold families through rational design.
    18. (2008). Energetics of divalent selectivity in a calcium channel: the ryanodine receptor case study.
    19. (2000). Evidence for a role of the lumenal M3-M4 loop in skeletal muscle Ca 2+ release channel (ryanodine receptor) activity and conductance.
    20. (2001). GROMACS 3.0: a package for molecular simulation and trajectory analysis.
    21. (1995). GROMACS: a message-passing parallel molecular-dynamics implementation.
    22. (2007). Identification of secondary structure elements in intermediate-resolution density maps.
    23. (1981). Interaction models for water in relation to protein hydration. In:
    24. (1998). Ion permeation and glutamate residues linked by Poisson-Nernst-Planck theory in L-type calcium channels.
    25. (1990). Ion-water interaction potentials derived from free energy perturbation simulations.
    26. (2001). Ligand-gated ion channels.
    27. (2001). Light at the end of the Ca 2+-release channel tunnel: structures and mechanisms involved in ion translocation in ryanodine receptor channels.
    28. (2004). Location of divergent region 2 on the three-dimensional structure of cardiac muscle ryanodine receptor/calcium release channel.
    29. (1997). Locations of calmodulin and FK506-binding protein on the threedimensional architecture of the skeletal muscle ryanodine receptor.
    30. (1999). Luminal loop of the ryanodine receptor: a pore-forming segment?
    31. (2006). Membrane protein simulations with a united-atom lipid and all-atom protein model: lipid-protein interactions, side chain transfer free energies and model proteins.
    32. (1993). Molecular determinants of Ca 2+ selectivity and ion permeation in L-type Ca 2+ channels.
    33. (1999). Molecular identification of the ryanodine receptor pore-forming segment.
    34. (1984). Molecular-dynamics with coupling to an external bath.
    35. (1989). Multiple conductance states of the purified calcium release channel complex from skeletal sarcoplasmic reticulum.
    36. (2004). Negatively charged amino acids within the intraluminal loop of ryanodine receptor are involved in the interaction with triadin.
    37. (2004). On the importance of atomic fluctuations, protein flexibility, and solvent in ion permeation.
    38. (2001). Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.
    39. (1993). Probing the structure of the conduction pathway of the sheep cardiac sarcoplasmic reticulum calcium-release channel with permeant and impermeant organic cations.
    40. (2002). Ryanodine receptor calcium release channels.
    41. (1997). Ryanodine receptors of striated muscles: a complex channel capable of multiple interactions.
    42. (2003). Sali A
    43. (2008). Single channel properties of heterotetrameric mutant RyR1 ion channels linked to core myopathies.
    44. (2001). Structural understanding of the transmembrane domains of inositol triphosphate receptors and ryanodine receptors towards calcium channeling.
    45. (2005). Structure of Ca 2+ release channel at 14 A ˚ resolution.
    46. (2004). Structure of the acrosomal bundle.
    47. (2003). The implementation of slab geometry for membrane-channel molecular dynamics simulations.
    48. (2002). The open pore conformation of potassium channels 1.
    49. (1988). The OPLS [optimized potentials for liquid simulations] potential functions for proteins, energy minimizations for crystals of cyclic peptides and crambin.
    50. (2005). The pore structure of the closed RyR1 channel.
    51. (1998). The structure of the potassium channel: molecular basis of K + conduction and selectivity.
    52. (2006). Two rings of negative charges in the cytosolic vestibule of type-1 ryanodine receptor modulate ion fluxes.
    53. (1996). Two structural configurations of the skeletal muscle calcium release channel.
    54. (2005). Two-dimensional crystallization of the ryanodine receptor Ca 2+ release channel on lipid membranes.

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