Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.75346
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Funding
- National Natural Science Foundation of China [32022073, 31972287]
- Natural Science Foundation of Tianjin City [19JCYBJC24500]
- Canadian Institutes of Health Research [PJT-159601]
- Canadian Institutes of Health Research Fellowship
- Michael Smith Foundation for Health Research Fellowship
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This study reveals the disease mechanism of several mutations in PLN by changing its conformation and weakening its interaction with PKA, leading to the reduction of its phosphorylation level. Additionally, another regulatory peptide, called ALN, also regulates SERCA activity through a similar mechanism mediated by PKA.
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.
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