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

• Published in: eLife Vol. 11
• Main Authors: Qin, Juan, Zhang, Jingfeng, Lin, Lianyun, Haji-Ghassemi, Omid, Lin, Zhi, Woycechowsky, Kenneth J, Van Petegem, Filip, Zhang, Yan, Yuchi, Zhiguang
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications, Ltd 17.03.2022; eLife Sciences Publications Ltd
• Subjects: Animals; Biochemistry and Chemical Biology; Calcium-Binding Proteins; Cardiomyopathy, Dilated; Cyclic AMP-Dependent Protein Kinases - metabolism; dilated cardiomyopathy; Mice; phospholamban; phosphorylation; protein kinase A; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Structural Biology and Molecular Biophysics; chemical biology; biochemistry; structural biology; phospholamban; molecular biophysics; protein kinase A; phosphorylation; E. coli; dilated cardiomyopathy
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.75346

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 Ca -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.