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

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. © 2022, Qin et al.

Citation

Juan Qin, Jingfeng Zhang, Lianyun Lin, Omid Haji-Ghassemi, Zhi Lin, Kenneth J Woycechowsky, Filip Van Petegem, Yan Zhang, Zhiguang Yuchi. Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy. eLife. 2022 Mar 17;11

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PMID: 35297759

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