Seminar - Prof. Andrew R. Marks
Towards a structural basis of complex disorders of heart, muscle and brain
The ryanodine receptors (RyR) are 3 MDa homotetrameric ion channels that mediate Ca2+ release and regulate critical signaling processes in many tissues (e.g. neurons, skeletal and cardiac muscle). In 1990, Dr. Marks cloned the RyR1 and in 2014 solved the structure of the RyR1 at 4.8 Å resolution that, for the first time, elucidates the channel domains, the pore and provides a mechanism for calcium dependent gating of the ion channel*. He has discovered several regulatory functions of RyR via protein interactions (e.g. FKBP12, phosphatases and kinases) and by post-translational modifications (phosphorylation and redox processes), leading to changes in channel gating properties and cellular Ca2+ homeostasis. These discoveries have led to mechanistic understanding of diseases such as heart failure, ventricular arrhythmias, muscular weakness and stress-induced cognitive dysfunction. Dr. Marks has developed RyR stabilizing compounds that show promise in animal disease models. Furthermore, he was instrumental in the research leading to development of rapamycin-eluting coronary stents that prevent restenosis after cardiac coronary intervention.
* Article in Nature: Zalk et al. Nature 517:44-9 (2015).
Dr. Marks is chairman of the Physiology and Cellular Biophysics department at Columbia University Medical Center in New York, and founding Director of the Clyde and Helen Wu Center for Molecular Cardiology. Following his M.D. degree from Harvard, he trained in internal medicine and cardiology at Massachusetts General Hospital where he also pursued postdoctoral research in molecular biology. Since 1997 he has been at Columbia University. Dr. Marks is a member of the National Academy of Sciences, USA.