Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy
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 mod...
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75346 |
| _version_ | 1797960533667741696 |
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| author | Juan Qin Jingfeng Zhang Lianyun Lin Omid Haji-Ghassemi Zhi Lin Kenneth J Woycechowsky Filip Van Petegem Yan Zhang Zhiguang Yuchi |
| author_facet | Juan Qin Jingfeng Zhang Lianyun Lin Omid Haji-Ghassemi Zhi Lin Kenneth J Woycechowsky Filip Van Petegem Yan Zhang Zhiguang Yuchi |
| author_sort | Juan Qin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T00:46:53Z |
| format | Article |
| id | doaj.art-7586687f069648989c8b379c95762a39 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T00:46:53Z |
| publishDate | 2022-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7586687f069648989c8b379c95762a392023-01-05T14:08:35ZengeLife Sciences Publications LtdeLife2050-084X2022-03-011110.7554/eLife.75346Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathyJuan Qin0https://orcid.org/0000-0002-6762-3988Jingfeng Zhang1Lianyun Lin2Omid Haji-Ghassemi3Zhi Lin4Kenneth J Woycechowsky5Filip Van Petegem6Yan Zhang7Zhiguang Yuchi8https://orcid.org/0000-0003-2595-9106Tianjin 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, ChinaWuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, ChinaTianjin 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, ChinaDepartment of Biochemistry and Molecular Biology, The Life Sciences Centre, University of British Columbia, Vancouver, CanadaSchool of Life Sciences, Tianjin University, Tianjin, ChinaTianjin 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, ChinaDepartment of Biochemistry and Molecular Biology, The Life Sciences Centre, University of British Columbia, Vancouver, CanadaTianjin 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, ChinaTianjin 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, ChinaSeveral 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.https://elifesciences.org/articles/75346protein kinase Aphospholambandilated cardiomyopathyphosphorylation |
| spellingShingle | Juan Qin Jingfeng Zhang Lianyun Lin Omid Haji-Ghassemi Zhi Lin Kenneth J Woycechowsky Filip Van Petegem Yan Zhang Zhiguang Yuchi Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy eLife protein kinase A phospholamban dilated cardiomyopathy phosphorylation |
| title | Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy |
| title_full | Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy |
| title_fullStr | Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy |
| title_full_unstemmed | Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy |
| title_short | Structures of PKA–phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy |
| title_sort | structures of pka phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy |
| topic | protein kinase A phospholamban dilated cardiomyopathy phosphorylation |
| url | https://elifesciences.org/articles/75346 |
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