Faculty Collaboration Database

Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca²⁺ and phosphorylation. Elife 2021 May 12;10

Date

05/13/2021

Pubmed ID

33978571

Pubmed Central ID

PMC8184213

DOI

10.7554/eLife.66226

Scopus ID

2-s2.0-85108020453 (requires institutional sign-in at Scopus site)   20 Citations

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.

Author List

Weber DK, Reddy UV, Wang S, Larsen EK, Gopinath T, Gustavsson MB, Cornea RL, Thomas DD, De Simone A, Veglia G

Author

Gopinath Tata PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Allosteric Regulation
Animals
Calcium
Calcium-Binding Proteins
Escherichia coli
Magnetic Resonance Spectroscopy
Membrane Proteins
Molecular Structure
Phosphorylation
Protein Conformation
Rabbits
Sarcoplasmic Reticulum
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Signal Transduction