Dynamics-Driven Allostery Underlies Ca2+-Mediated Release of SERCA Inhibition by Phospholamban

Raguimova, Olga N.; Aguayo‐Ortiz, Rodrigo; Robia, Seth L.; Espinoza-Fonseca, L. Michel

doi:10.1016/j.bpj.2020.09.014

Cited by 12 publications

(15 citation statements)

References 68 publications

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“…We conclude that PLB phosphorylation serves as an allosteric molecular switch that releases inhibitory contacts and strings together the catalytic elements required for SERCA activation. Based on these findings, we provide novel hypotheses that can be tested by functional mutagenesis studies to validate the putative SERCA site Arg324/Lys328, and also by complementary spectroscopy and simulation studies [34] to establish the structure-function relationships of SERCA regulation by PLB. The mechanistic insights from this study will likely have important implications for our understanding of the molecular switches that underly regulation of Ca 2+ transport, and will also help understand the structural features required for therapeutic modulation of SERCA in the heart.…”

Section: Discussionmentioning

confidence: 99%

“…We excluded the first 0.2 µ s from each MD trajectory to avoid biases associated with the initial configuration of the SERCA-pPLB complex. We also generated an MD ensemble of the unphosphorylated PLB bound to SERCA by combining five MD trajectories generated previously by our group into a single trajectory (total simulation time of 17.8 µ s [34]). These trajectories are used as a control here to resolve precise structural changes induced by PLB phosphorylation.…”

Section: Phosphorylated Plb Induces Functional Transitions In Sercamentioning

confidence: 99%

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Atomistic Structure and Dynamics of the Ca2+-ATPase Bound to Phosphorylated Phospholamban

Aguayo‐Ortiz

Espinoza-Fonseca

2020

IJMS

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Sarcoplasmic reticulum Ca2+-ATPase (SERCA) and phospholamban (PLB) are essential components of the cardiac Ca2+ transport machinery. PLB phosphorylation at residue Ser16 (pSer16) enhances SERCA activity in the heart via an unknown structural mechanism. Here, we report a fully atomistic model of SERCA bound to phosphorylated PLB and study its structural dynamics on the microsecond time scale using all-atom molecular dynamics simulations in an explicit lipid bilayer and water environment. The unstructured N-terminal phosphorylation domain of PLB samples different orientations and covers a broad area of the cytosolic domain of SERCA but forms a stable complex mediated by pSer16 interactions with a binding site formed by SERCA residues Arg324/Lys328. PLB phosphorylation does not affect the interaction between the transmembrane regions of the two proteins; however, pSer16 stabilizes a disordered structure of the N-terminal phosphorylation domain that releases key inhibitory contacts between SERCA and PLB. We found that PLB phosphorylation is sufficient to guide the structural transitions of the cytosolic headpiece that are required to produce a competent structure of SERCA. We conclude that PLB phosphorylation serves as an allosteric molecular switch that releases inhibitory contacts and strings together the catalytic elements required for SERCA activation. This atomistic model represents a vivid atomic-resolution visualization of SERCA bound to phosphorylated PLB and provides previously inaccessible insights into the structural mechanism by which PLB phosphorylation releases SERCA inhibition in the heart.

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Section: Discussionmentioning

confidence: 99%

Section: Phosphorylated Plb Induces Functional Transitions In Sercamentioning

confidence: 99%

Atomistic Structure and Dynamics of the Ca2+-ATPase Bound to Phosphorylated Phospholamban

Aguayo‐Ortiz

Espinoza-Fonseca

2020

IJMS

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“…Phosphorylated pentamer PLB loses its inhibitory effect on SERCA2a. The SERCA/PLB ratio accurately represents myocardial diastolic and systolic activity, and changes in this ratio directly reflect changes in cardiac function [6]. In a study of ten patients with stress-induced cardiomyopathy, sarcolipin, which is expressed primarily in atrial myocytes, has been found to be highly expressed in left ventricular cardiomyocytes, and to decrease SERCA's activity and affinity for calcium ions by acting in collaboration with phosphorylated PLB; however, the expression of the sodium calcium exchanger NCX and ryanodine receptor 2 (RyR2) has not been found to increase [7].…”

Section: Calcium Disordersmentioning

confidence: 99%

Mechanisms of Myocardial Stunning in Stress-Induced Cardiomyopathy

Yin

2022

CVIA

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Stress-induced cardiomyopathy, in contrast to acute myocardial infarction, is a type of acute heart failure characterizedby reversible left ventricular dysfunction. Cardiac imaging primarily reveals left ventricle myocardial stunning, 81.7%of which is apical type. Emotional or psychological stress usually precedes the onset of stress-induced cardiomyopathy,which is increasingly being recognized as a unique neurogenic myocardial stunning disease. To distinguish betweenacute myocardial infarction and acute viral or auto-immune myocarditis, this review summarizes specific mechanismsof myocardial stunning in stress-induced cardiomyopathy, such as calcium disorders, metabolic alterations, anatomicaland histological variations in different parts of the left ventricle, and microvascular dysfunction.

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“…These have become increasingly useful as growing processing power enables longer simulations of larger systems. The timescale of molecular dynamics now overlaps the time regimen of interesting structural transitions ( Raguimova et al, 2020 ), and analytical approaches provide exploration of the energy landscape that governs key conformational changes ( Das et al, 2017 ). In addition, we anticipate that new membrane protein–protein docking methods ( Alford et al, 2015 ) will be useful for quantifying the energetics of binding of FXYDs to different αβ complexes, generating testable hypotheses about novel modes of tissue-specific interactions.…”

Section: Introductionmentioning

confidence: 99%

FXYD proteins and sodium pump regulatory mechanisms

Yap

Šeflová

Sweazey

et al. 2021

Journal of General Physiology

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The sodium/potassium-ATPase (NKA) is the enzyme that establishes gradients of sodium and potassium across the plasma membrane. NKA activity is tightly regulated for different physiological contexts through interactions with single-span transmembrane peptides, the FXYD proteins. This diverse family of regulators has in common a domain containing a Phe-X-Tyr-Asp (FXYD) motif, two conserved glycines, and one serine residue. In humans, there are seven tissue-specific FXYD proteins that differentially modulate NKA kinetics as appropriate for each system, providing dynamic responsiveness to changing physiological conditions. Our understanding of how FXYD proteins contribute to homeostasis has benefitted from recent advances described in this review: biochemical and biophysical studies have provided insight into regulatory mechanisms, genetic models have uncovered remarkable complexity of FXYD function in integrated physiological systems, new posttranslational modifications have been identified, high-resolution structural studies have revealed new details of the regulatory interaction with NKA, and new clinical correlations have been uncovered. In this review, we address the structural determinants of diverse FXYD functions and the special roles of FXYDs in various physiological systems. We also discuss the possible roles of FXYDs in protein trafficking and regulation of non-NKA targets.

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Dynamics-Driven Allostery Underlies Ca2+-Mediated Release of SERCA Inhibition by Phospholamban

Cited by 12 publications

References 68 publications

Atomistic Structure and Dynamics of the Ca2+-ATPase Bound to Phosphorylated Phospholamban

Atomistic Structure and Dynamics of the Ca2+-ATPase Bound to Phosphorylated Phospholamban

Mechanisms of Myocardial Stunning in Stress-Induced Cardiomyopathy

FXYD proteins and sodium pump regulatory mechanisms

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