Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
| Autor: | Weber, Daniel K, Reddy, U Venkateswara, Wang, Songlin, Larsen, Erik K, Gopinath, Tata, Gustavsson, Martin B, Cornea, Razvan L, Thomas, David D, De Simone, Alfonso, Veglia, Gianluigi |
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| Přispěvatelé: | Weber, Daniel K, Reddy, U Venkateswara, Wang, Songlin, Larsen, Erik K, Gopinath, Tata, Gustavsson, Martin B, Cornea, Razvan L, Thomas, David D, De Simone, Alfonso, Veglia, Gianluigi |
| Rok vydání: | 2021 |
| Předmět: |
Magnetic Resonance Spectroscopy
Protein Conformation Structural Biology and Molecular Biophysics Sarcoplasmic Reticulum Calcium-Transporting ATPase Rabbit 01 natural sciences structural biology membrane protein Biology (General) Phosphorylation Calcium-Binding Protein 0303 health sciences Molecular Structure Chemistry General Neuroscience General Medicine Transmembrane protein Phospholamban Sarcoplasmic Reticulum cardiovascular system Medicine Rabbits Signal transduction Research Article topological allostery Signal Transduction endocrine system SERCA QH301-705.5 Science Allosteric regulation 010402 general chemistry General Biochemistry Genetics and Molecular Biology Sarcoplasmic Reticulum Calcium-Transporting ATPases 03 medical and health sciences Allosteric Regulation Escherichia coli Animals oriented solid 030304 developmental biology General Immunology and Microbiology Animal Calcium-Binding Proteins E. coli Membrane Proteins Sarcoplasmic reticulum membrane 0104 chemical sciences molecular biophysic Membrane protein Biophysics Calcium state NMR |
| Zdroj: | eLife eLife, Vol 10 (2021) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.66226 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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