F A C U L T Y   P R O F I L E 

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Assistant Professor of Physiology and Cellular Biophysics (in Anesthesiology and the Irving Institute for Clinical and Translational Research)

Structural characterization of membrane proteins mediating and modulating intracellular calcium release


Current Research

Intracellular calcium signaling, mediated by release of calcium from intracellular stores, is involved in many fundamental biological processes, amongst which perhaps most prominent is the coupling of nervous excitation to muscle contraction (E-C coupling). A key goal of the laboratory is to understand the mechanism by which intracellular calcium release is triggered, modulated and terminated. We use X-ray crystallography and cryoelectron microscopy (CryoEM) to investigate the structure and dynamics of the molecular machines involved in such process, including amongst others the ryanodine receptor (RyR), which mediates intracellular Ca2+ release during E-C coupling.

We and others have described structures of the isolated ryanodine receptor in various states – closed, open, and bound to activating ligands. One of the key issues we wish to address with further work is to investigate the skeletal muscle ryanodine receptor in the context of both the transmembrane protein binding partners around it, and the cell as a whole.

The ultimate goal of our research is a structural understanding of how the voltage gated Ca2+ channels on the plasma membrane mechanically couple to the ryanodine receptor and directly control gating of the receptor, and how adjacent RyRs in the paracrystalline arrays that have been observed at the terminal cisternae interact with one another and signal cooperatively.

Selected Publications

Zalk R*, Clarke OB*, des Georges A*, Grassucci RA, Reiken S, Mancia F, Hendrickson WA, Frank J, Marks AR. Structure of a mammalian ryanodine receptor. Nature. 2015; 517(7532):44-9.

Chen Y*, Clarke OB*, Kim J, Stowe S, Kim YK, Assur Z, Cavalier M, Godoy-Ruiz R, von Alpen DC, Manzini C, Blaner WS, Frank J, Quadro L, Weber DJ, Shapiro L, Hendrickson WA, Mancia F. Structure of the STRA6 receptor for retinol uptake. Science. 2016. 353(6302)

des Georges A*, Clarke OB*, Zalk R*, Yuan Q, Condon KJ, Grassucci RA, Hendrickson WA, Marks AR, Frank J. Structural Basis for Gating and Activation of RyR1. Cell. 2016; 167(1):145-157.e17

Clarke OB, Tomasek D, Jorge CD, Dufrisne MB, Kim M, Banerjee S, Rajashankar KR, Shapiro L, Hendrickson WA, Santos H, Mancia F. Structural basis for phosphatidylinositol-phosphate biosynthesis. Nat Comms. 2015; 6:8505.

A full list of publications can be obtained here: