Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
- University of Minnesota, United States
- Imperial College London, United Kingdom
Abstract
Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to b-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.
Data availability
Here are the links/codes for data deposited:BMRB:50718:Monomeric phospholamban in oriented bicelles;50719:Monomeric phosphorylated phospholamban in oriented bicelles;50720:Phospholamban bound to SERCA in oriented bicelles (calcium-free E2 state);50721:Phospholamban bound to SERCA in oriented bicelles (calcium-bound E1 state);50722:Phosphorylated phospholamban bound to SERCA in oriented bicelles(calcium-free E2 state);50723:Phosphorylated phospholamban bound to SERCA in oriented bicelles(calcium-bound E1 state).And the link to DRUM:https://conservancy.umn.edu/handle/11299/218010
Article and author information
Author details
Funding
National Institutes of Health (GM064742)
- Gianluigi Veglia
National Institutes of Health (HL144100)
- Gianluigi Veglia
National Institutes of Health (HL139065)
- David D Thomas
National Institutes of Health (AG026160)
- Razvan L Cornea
European Commission (BioDisOrder - 819644)
- Alfonso De Simone
American Heart Association (19POST34420009)
- Daniel K Weber
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Weber et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
eLife 10:e66226.
https://doi.org/10.7554/eLife.66226
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