Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation

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

Research output: Contribution to journalArticlepeer-review

Abstract

Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-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 Ca2+-ATPase (SERCA), keeping this enzyme’s function within a narrow physiological window. PLN phosphorylation by cAMP-dependent protein kinase A or increase in Ca2+ 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 Ca2+ transport. Our findings address long- standing questions about SERCA regulation, epitomizing a signal transduction mechanism operated by posttranslationally modified bitopic membrane proteins.

Original languageEnglish (US)
Article numbere66226
JournaleLife
Volume10
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
This work was supported by the National Institute of Health grants R01 GM064742 and R01 HL144100 to GV and R01HL139065 and R37AG026160 to DDT and RLC; and European Research Council (CoG - BioDisOrder - 819644) funding to ADS DW was supported by an American Heart Association Postdoctoral Fellowship (19POST34420009). The authors thank Dr. Sanz-Hernández for his initial contribution to the project.

Publisher Copyright:
© Weber et al.

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