Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
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Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation. / Weber, Daniel K; Reddy, U Venkateswara; Wang, Songlin; Larsen, Erik K; Gopinath, Tata; Gustavsson, Martin; Cornea, Razvan L; Thomas, David D; De Simone, Alfonso; Veglia, Gianluigi.
I: eLife, Bind 10, 12.05.2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
AU - Weber, Daniel K
AU - Reddy, U Venkateswara
AU - Wang, Songlin
AU - Larsen, Erik K
AU - Gopinath, Tata
AU - Gustavsson, Martin
AU - Cornea, Razvan L
AU - Thomas, David D
AU - De Simone, Alfonso
AU - Veglia, Gianluigi
N1 - © 2021, Weber et al.
PY - 2021/5/12
Y1 - 2021/5/12
N2 - 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.
AB - 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.
KW - Allosteric Regulation
KW - Animals
KW - Calcium/metabolism
KW - Calcium-Binding Proteins/chemistry
KW - Escherichia coli
KW - Magnetic Resonance Spectroscopy
KW - Membrane Proteins/metabolism
KW - Molecular Structure
KW - Phosphorylation
KW - Protein Conformation
KW - Rabbits
KW - Sarcoplasmic Reticulum
KW - Sarcoplasmic Reticulum Calcium-Transporting ATPases/chemistry
KW - Signal Transduction
U2 - 10.7554/eLife.66226
DO - 10.7554/eLife.66226
M3 - Journal article
C2 - 33978571
VL - 10
JO - eLife
JF - eLife
SN - 2050-084X
ER -
ID: 329434446