Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy
- Tianjin University, China
- Chinese Academy of Sciences, China
- University of British Columbia, Canada
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).
Article and author information
Author details
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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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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