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.
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Authors | Juan Qin, Jingfeng Zhang, Lianyun Lin, Omid Haji-Ghassemi, Zhi Lin, Kenneth J Woycechowsky, Filip Van Petegem, Yan Zhang, Zhiguang Yuchi |
Journal | eLife
(Elife)
Vol. 11
(03 17 2022)
ISSN: 2050-084X [Electronic] England |
PMID | 35297759
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2022, Qin et al. |
Chemical References |
- Calcium-Binding Proteins
- phospholamban
- Cyclic AMP-Dependent Protein Kinases
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Topics |
- Animals
- Calcium-Binding Proteins
- Cardiomyopathy, Dilated
- Cyclic AMP-Dependent Protein Kinases
(metabolism)
- Mice
- Sarcoplasmic Reticulum
(metabolism)
- Sarcoplasmic Reticulum Calcium-Transporting ATPases
(genetics, metabolism)
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