Structural Basis for Allosteric Control of the SERCA-Phospholamban Membrane Complex by Ca and Phosphorylation

Overview

Journal Elife

Specialty Biology

Date 2021 May 12

PMID 33978571

Citations 11

Authors

Daniel K Weber

U Venkateswara Reddy

Songlin Wang

Erik K Larsen

Tata Gopinath

Martin B Gustavsson

Razvan L Cornea

David D Thomas

Alfonso De Simone

Gianluigi Veglia

Affiliations

Soon will be listed here.

Abstract

Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca-transport response to β-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 Ca-ATPase (SERCA), keeping this enzyme's function within a narrow physiological window. PLN phosphorylation by cAMP-dependent protein kinase A or increase in Ca concentration reverses the inhibitory effects through an unknown mechanism. Using oriented-sample solid-state NMR spectroscopy and replica-averaged NMR-restrained structural refinement, we reveal that phosphorylation of PLN's cytoplasmic regulatory domain signals the disruption of several inhibitory contacts at the transmembrane binding interface of the SERCA-PLN complex that are propagated to the enzyme's active site, augmenting Ca transport. Our findings address long-standing questions about SERCA regulation, epitomizing a signal transduction mechanism operated by posttranslationally modified bitopic membrane proteins.

Citing Articles

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