Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency; Collaborative Innovation Center of Chemical Science and Engineering; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
Jingfeng Zhang
Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China
Lianyun Lin
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency; Collaborative Innovation Center of Chemical Science and Engineering; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
Omid Haji-Ghassemi
Department of Biochemistry and Molecular Biology, The Life Sciences Centre, University of British Columbia, Vancouver, Canada
Zhi Lin
School of Life Sciences, Tianjin University, Tianjin, China
Kenneth J Woycechowsky
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency; Collaborative Innovation Center of Chemical Science and Engineering; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
Filip Van Petegem
Department of Biochemistry and Molecular Biology, The Life Sciences Centre, University of British Columbia, Vancouver, Canada
Yan Zhang
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency; Collaborative Innovation Center of Chemical Science and Engineering; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency; Collaborative Innovation Center of Chemical Science and Engineering; School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China; Department of Molecular Pharmacology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer, Tianjin, China
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.
