Apr 27, 2020

Dynamics-driven allostery underlies pre-activation of the regulatory Ca2+-ATPase/phospholamban complex

BioRxiv : the Preprint Server for Biology
O. N. RaguimovaL. Michel Espinoza-Fonseca


Sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) and phospholamban (PLB) are essential for intracellular 2+ transport in myocytes. 2+-dependent activation of SERCA-PLB provides a rheostat function that regulates cytosolic and SR 2+ levels. While experimental and computational studies alone have led to a greater insight into the mechanisms for SERCA-PLB regulation, the structural changes induced by 2+ binding and how those are communicated to couple enzymatic activity with active transport remain poorly understood. Therefore, we have performed atomistic simulations totaling 32.7 s and cell-based intramolecular fluorescence resonance energy transfer (FRET) experiments to determine structural changes of PLB-bound SERCA in response to 2+ binding. Complementary simulations and experiments showed structural disorder underlies PLB inhibition of SERCA, and 2+ binding is sufficient to shift the protein population toward a structurally ordered state of the complex. This structural transition results in a redistribution of structural states toward a partially closed conformation of SERCA's cytosolic headpiece. Closure is accompanied by functional interactions between the N-domain {beta}5-{beta}6 loop and the A-domain. Regulation of these k...Continue Reading

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