1. Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy.
- Author
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Juan Qin, Jingfeng Zhang, Lianyun Lin, Haji-Ghassemi, Omid, Zhi Lin, Woycechowsky, Kenneth J., Van Petegem, Filip, Yan Zhang, and Zhiguang Yuchi
- Subjects
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DILATED cardiomyopathy , *PEPTIDES , *CATALYTIC domains , *PROTEIN kinases , *PHOSPHOLAMBAN - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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