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Crystal structure of PKAc-A11E complexCrystal structure of PKAc-A11E complex
Structural highlights
DiseasePPLA_HUMAN Defects in PLN are the cause of cardiomyopathy dilated type 1P (CMD1P) [MIM:609909. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[1] [2] Defects in PLN are the cause of familial hypertrophic cardiomyopathy type 18 (CMH18) [MIM:613874. CMH18 is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.[3] FunctionPPLA_HUMAN Phospholamban has been postulated to regulate the activity of the calcium pump of cardiac sarcoplasmic reticulum. Publication Abstract from PubMedSeveral 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(2+)-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. Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy.,Qin J, Zhang J, Lin L, Haji-Ghassemi O, Lin Z, Woycechowsky KJ, Van Petegem F, Zhang Y, Yuchi Z Elife. 2022 Mar 17;11:e75346. doi: 10.7554/eLife.75346. PMID:35297759[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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