Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
Research output: Contribution to journal › Journal article › Research › peer-review
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 language | English |
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Journal | eLife |
Volume | 10 |
ISSN | 2050-084X |
DOIs | |
Publication status | Published - 12 May 2021 |
Externally published | Yes |
Bibliographical note
© 2021, Weber et al.
- Allosteric Regulation, Animals, Calcium/metabolism, Calcium-Binding Proteins/chemistry, Escherichia coli, Magnetic Resonance Spectroscopy, Membrane Proteins/metabolism, Molecular Structure, Phosphorylation, Protein Conformation, Rabbits, Sarcoplasmic Reticulum, Sarcoplasmic Reticulum Calcium-Transporting ATPases/chemistry, Signal Transduction
Research areas
ID: 329434446