ArticleBiophysical journal2015
Atomic-level mechanisms for phospholamban regulation of the calcium pump.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 39 citations in OpenAlex.
- Allosteric Modulation of SERCA Pumps in Health and Disease: Structural Dynamics, Posttranslational Modifications, and Therapeutic Potential.Journal of molecular biology · 2025Review
- Article
- Multistate Kinetic Model of the Sodium-Potassium ATPase.The journal of physical chemistry. B · 2025Article
- Mechanisms for cardiac calcium pump activation by its substrate and a synthetic allosteric modulator using fluorescence lifetime imaging.PNAS nexus · 2024Article
- Structural Basis for the Function of the C-Terminal Proton Release Pathway in the Calcium Pump.International journal of molecular sciences · 2021Article
- Sarcolipin Exhibits Abundant RNA Transcription and Minimal Protein Expression in Horse Gluteal Muscle.Veterinary sciences · 2020Article
- Dynamics-Driven Allostery Underlies CaBiophysical journal · 2020Article
- Atomistic Structure and Dynamics of the CaInternational journal of molecular sciences · 2020Article
- Interaction of a Sarcolipin Pentamer and Monomer with the Sarcoplasmic Reticulum Calcium Pump, SERCA.Biophysical journal · 2020Article
- A hallmark of phospholamban functional divergence is located in the N-terminal phosphorylation domain.Computational and structural biotechnology journal · 2020Article
- Deciphering the Mechanism of Inhibition of SERCA1a by Sarcolipin Using Molecular Simulations.Frontiers in molecular biosciences · 2020Article
- Probing the effects of nonannular lipid binding on the stability of the calcium pump SERCA.Scientific reports · 2019Article
- The Phospholamban Pentamer Alters Function of the Sarcoplasmic Reticulum Calcium Pump SERCA.Biophysical journal · 2019Article
- Proton Countertransport and Coupled Gating in the Sarcoplasmic Reticulum Calcium Pump.Journal of molecular biology · 2018Article
- Structural basis for relief of phospholamban-mediated inhibition of the sarcoplasmic reticulum CaThe Journal of biological chemistry · 2018Article
- Preexisting domain motions underlie protonation-dependent structural transitions of the P-type CaPhysical chemistry chemical physics : PCCP · 2017Article
- The CaMolecular bioSystems · 2017Review
- Sarcolipin Promotes Uncoupling of the SERCA CaBiochemistry · 2016Article
- Structure of myosin filaments from relaxedScience advances · 2016Article
- Hide and Seek: Protein-coding Sequences Inside "Non-coding" RNAs.Genomics, proteomics & bioinformatics · 2016Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
We performed protein pKa calculations and molecular dynamics (MD) simulations of the calcium pump (sarcoplasmic reticulum Ca(2+)-ATPase (SERCA)) in complex with phospholamban (PLB). X-ray crystallography studies have suggested that PLB locks SERCA in a low-Ca(2+)-affinity E2 state that is incompatible with metal-ion binding, thereby blocking the conversion toward a high-Ca(2+)-affinity E1 state. Estimation of pKa values of the acidic residues in the transport sites indicates that at normal intracellular pH (7.1-7.2), PLB-bound SERCA populates an E1 state that is deprotonated at residues E309 and D800 yet protonated at residue E771. We performed three independent microsecond-long MD simulations to evaluate the structural dynamics of SERCA-PLB in a solution containing 100 mM K(+) and 3 mM Mg(2+). Principal component analysis showed that PLB-bound SERCA lies exclusively along the structural ensemble of the E1 state. We found that the transport sites of PLB-bound SERCA are completely exposed to the cytosol and that K(+) ions bind transiently (≤5 ns) and nonspecifically (nine different positions) to the two transport sites, with a total occupancy time of K(+) in the transport sites of 80%. We propose that PLB binding to SERCA populates a novel (to our knowledge) E1 intermediate, E1⋅H(+)771. This intermediate serves as a kinetic trap that controls headpiece dynamics and depresses the structural transitions necessary for Ca(2+)-dependent activation of SERCA. We conclude that PLB-mediated regulation of SERCA activity in the heart results from biochemical and structural transitions that occur primarily in the E1 state of the pump.
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