1. Structural Biology and Molecular Biophysics

Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation

  1. Daniel K Weber
  2. U Venkateswara Reddy
  3. Songlin Wang
  4. Erik K Larsen
  5. Tata Gopinath
  6. Martin B Gustavsson
  7. Razvan L Cornea
  8. David D Thomas
  9. Alfonso De Simone
  10. Gianluigi Veglia  Is a corresponding author
  1. University of Minnesota, United States
  2. Imperial College London, United Kingdom
https://doi.org/10.7554/eLife.66226
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Cite this article
  1. Daniel K Weber
  2. U Venkateswara Reddy
  3. Songlin Wang
  4. Erik K Larsen
  5. Tata Gopinath
  6. Martin B Gustavsson
  7. Razvan L Cornea
  8. David D Thomas
  9. Alfonso De Simone
  10. Gianluigi Veglia
(2021)
Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
eLife 10:e66226.
https://doi.org/10.7554/eLife.66226
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Abstract

Phospholamban (PLN) is a mini-membrane protein that directly controls the cardiac Ca2+-transport response to b-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.

Data availability

Here are the links/codes for data deposited:BMRB:50718:Monomeric phospholamban in oriented bicelles;50719:Monomeric phosphorylated phospholamban in oriented bicelles;50720:Phospholamban bound to SERCA in oriented bicelles (calcium-free E2 state);50721:Phospholamban bound to SERCA in oriented bicelles (calcium-bound E1 state);50722:Phosphorylated phospholamban bound to SERCA in oriented bicelles(calcium-free E2 state);50723:Phosphorylated phospholamban bound to SERCA in oriented bicelles(calcium-bound E1 state).And the link to DRUM:https://conservancy.umn.edu/handle/11299/218010

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Author details

  1. Daniel K Weber

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. U Venkateswara Reddy

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Songlin Wang

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Erik K Larsen

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Tata Gopinath

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Martin B Gustavsson

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Razvan L Cornea

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. David D Thomas

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8822-2040

  9. Alfonso De Simone

    Division of Molecular Biosciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8789-9546

  10. Gianluigi Veglia

    Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    For correspondence
    vegli001@umn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2795-6964

Funding

National Institutes of Health (GM064742)

  • Gianluigi Veglia

National Institutes of Health (HL144100)

  • Gianluigi Veglia

National Institutes of Health (HL139065)

  • David D Thomas

National Institutes of Health (AG026160)

  • Razvan L Cornea

European Commission (BioDisOrder - 819644)

  • Alfonso De Simone

American Heart Association (19POST34420009)

  • Daniel K Weber

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Volker Dötsch, Goethe University, Germany

Version history

  1. Received: January 4, 2021
  2. Accepted: May 10, 2021
  3. Accepted Manuscript published: May 12, 2021 (version 1)
  4. Version of Record published: June 7, 2021 (version 2)

Copyright

© 2021, Weber et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Daniel K Weber
  2. U Venkateswara Reddy
  3. Songlin Wang
  4. Erik K Larsen
  5. Tata Gopinath
  6. Martin B Gustavsson
  7. Razvan L Cornea
  8. David D Thomas
  9. Alfonso De Simone
  10. Gianluigi Veglia
(2021)
Structural basis for allosteric control of the SERCA-Phospholamban membrane complex by Ca2+ and phosphorylation
eLife 10:e66226.
https://doi.org/10.7554/eLife.66226

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