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

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 additio

SUBMITTER: Qin J 

PROVIDER: S-EPMC8970585 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature