1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy

  1. Juan Qin
  2. Jingfeng Zhang
  3. Lianyun Lin
  4. Omid Haji-Ghassemi
  5. Zhi Lin
  6. Kenneth J Woycechowsky
  7. Filip Van Petegem
  8. Yan Zhang  Is a corresponding author
  9. Zhiguang Yuchi  Is a corresponding author
  1. Tianjin University, China
  2. Chinese Academy of Sciences, China
  3. University of British Columbia, Canada
https://doi.org/10.7554/eLife.75346
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Cite this article
  1. Juan Qin
  2. Jingfeng Zhang
  3. Lianyun Lin
  4. Omid Haji-Ghassemi
  5. Zhi Lin
  6. Kenneth J Woycechowsky
  7. Filip Van Petegem
  8. Yan Zhang
  9. Zhiguang Yuchi
(2022)
Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy
eLife 11:e75346.
https://doi.org/10.7554/eLife.75346
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Abstract

Several mutations identified in phospholamban (PLN) have been linked to familial dilated cardiomyopathy (DCM) and heart failure, yet the underlying molecular mechanism remains controversial. PLN interacts with sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and regulates calcium uptake, which is modulated by the protein kinase A (PKA)-dependent phosphorylation of PLN during the fight-or-flight response. Here, we present the crystal structures of the catalytic domain of mouse PKA in complex with wild-type and DCM-mutant PLNs. Our structures, combined with the results from other biophysical and biochemical assays, reveal a common disease mechanism: the mutations in PLN reduce its phosphorylation level by changing its conformation and weakening its interactions with PKA. In addition, we demonstrate that another more ubiquitous SERCA-regulatory peptide, called another-regulin (ALN), shares a similar mechanism mediated by PKA in regulating SERCA activity.

Data availability

Diffraction data have been deposited in PDB under the accession code: PKAc-WT PLN (PDB 7E0Z); PKAc-PLN R9C (PDB 7E11); PKAc-PLN A11E (PDB 7E12).

The following data sets were generated

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Author details

  1. Juan Qin

    School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Jingfeng Zhang

    Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Lianyun Lin

    School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.

  4. Omid Haji-Ghassemi

    Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.

  5. Zhi Lin

    School of Life Sciences, Tianjin University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Kenneth J Woycechowsky

    School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Filip Van Petegem

    Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.

  8. Yan Zhang

    School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
    For correspondence
    yan.zhang@tju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

  9. Zhiguang Yuchi

    School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
    For correspondence
    yuchi@tju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2595-9106

Funding

National Natural Science Foundation of China (32022073)

  • Zhiguang Yuchi

National Natural Science Foundation of China (31972287)

  • Zhiguang Yuchi

Natural Science Foundation of Tianjin City (19JCYBJC24500)

  • Zhiguang Yuchi

Canadian Institutes of Health Research (PJT-159601)

  • Filip Van Petegem

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

Copyright

© 2022, Qin 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. Juan Qin
  2. Jingfeng Zhang
  3. Lianyun Lin
  4. Omid Haji-Ghassemi
  5. Zhi Lin
  6. Kenneth J Woycechowsky
  7. Filip Van Petegem
  8. Yan Zhang
  9. Zhiguang Yuchi
(2022)
Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy
eLife 11:e75346.
https://doi.org/10.7554/eLife.75346

Share this article

https://doi.org/10.7554/eLife.75346

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