ArticlePloS one2014
Comparison of the structure and function of phospholamban and the arginine-14 deficient mutant associated with dilated cardiomyopathy.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- PLN-L31A/I40A for the treatment of inherited heart disease caused by PLN-R14del mutations.Acta pharmacologica Sinica · 2026Article
- Altered endoplasmic reticulum calcium loading in human PLN-R14del cardiomyopathy.Frontiers in cell and developmental biology · 2025Article
- Genetic landscape of phospholamban cardiomyopathies.Frontiers in cell and developmental biology · 2025Review
- The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion.Cellular and molecular life sciences : CMLS · 2024Article
- Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation.JACC. Basic to translational science · 2024Review
- Nuclear Calcium in Cardiac (Patho)Physiology: Small Compartment, Big Impact.Biomedicines · 2023Review
- Phospholamban R14del disease: The past, the present and the future.Frontiers in cardiovascular medicine · 2023Review
- Aberrant PLN-R14del Protein Interactions Intensify SERCA2a Inhibition, Driving Impaired CaInternational journal of molecular sciences · 2022Article
- Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits.International journal of molecular sciences · 2021Review
- Phospholamban cardiomyopathy: a Canadian perspective on a unique population.Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation · 2019Article
- Dysfunctional conformational dynamics of protein kinase A induced by a lethal mutant of phospholamban hinder phosphorylation.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Phospholamban (PLB) is a pentameric protein that plays an important role in regulating cardiac contractility via a reversible inhibitory association with the sarcoplasmic reticulum Ca2+ATPase (SERCA), the enzyme responsible for maintaining correct calcium homeostasis. Here we study the functional and biophysical characteristics of a PLB mutant associated with human dilated cardiomyopathy (DCM), with a deletion of arginine at position 14 (PLBR14Δ). In agreement with recent findings, we find that PLBR14Δ has a reduced inhibitory effect on SERCA compared to wild type PLB (PLBWT) when reconstituted into lipid membranes. The mutation also leads to a large reduction in the protein kinase A-catalysed phosphorylation of Ser-16 in the cytoplasmic domain of PLBR14Δ. Measurements on SERCA co-reconstituted with an equimolar mixture of PLBWT and PLBR14Δ (representing the lethal heterozygous state associated with DCM) indicates that the loss-of-function mutation has a dominant effect on PLBWT functionality and phosphorylation capacity, suggesting that mixed PLBWT/PLBR14Δ pentamers are formed that have characteristics typical of the mutant protein. Structural and biophysical analysis of PLBR14Δ indicates that the mutation perturbs slightly the helical structure of the PLB cytoplasmic domain and reduces its affinity for the phospholipid bilayer surface, thereby altering the orientation of the cytoplasmic domain relative to the wild-type protein. These results indicate that the structure and function consequences of the R14 deletion have profound effects on the regulation of SERCA which may contribute to the aetiology of DCM.
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