A Bitopic Miniprotein Regulates a Membrane-Embedded Enzyme via Topological Allostery

Published: Aug. 28, 2020, 7:02 a.m.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.28.271940v1?rss=1 Authors: Weber, D. K., Hernandez, M. S., Reddy, V. U., Wang, S., Larsen, E. K., Tata, G., Gustavsson, M., Cornea, R. L., Thomas, D. D., De Simone, A., Veglia, G. Abstract: Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to {beta}-adrenergic stimulation, thus modulating cardiac output during the fight-or-flight response. In the sarcoplasmic reticulum membrane, PLN binds to the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), keeping this enzyme's function within a narrow physiological window. PLN phosphorylation or increase in Ca2+ concentration reverses the inhibitory effects. Despite a plethora of X-ray studies, the structural mechanism of SERCA regulation by PLN remains unknown. Using solid-state NMR spectroscopy and replica-averaged NMR-restrained structural refinement, we found that the transmembrane region of PLN is in equilibrium between inhibitory and non-inhibitory topologies within SERCA's binding groove. Phosphorylation of PLN at Ser16, or increase in Ca2+ concentration, shifts the equilibrium toward the non-inhibitory topologies, augmenting Ca2+ transport and muscle contractility. This type of allosteric regulation, via topological changes (topological allostery), may constitute a general mechanism for the other regulins that modulate SERCA activity in cardiac and skeletal muscle. Copy rights belong to original authors. Visit the link for more info