Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA
The sarco-plasmic reticulum calcium pump (SERCA) plays a critical role in the contraction-relaxation cycle of muscle. In cardiac muscle, SERCA is regulated by the inhibitor phospholamban. A new regulator, dwarf open reading frame (DWORF), has been reported to displace phospholamban from SERCA. Here,...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/65545 |
| _version_ | 1811180621405356032 |
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| author | M'Lynn E Fisher Elisa Bovo Rodrigo Aguayo-Ortiz Ellen E Cho Marsha P Pribadi Michael P Dalton Nishadh Rathod M Joanne Lemieux L Michel Espinoza-Fonseca Seth L Robia Aleksey V Zima Howard S Young |
| author_facet | M'Lynn E Fisher Elisa Bovo Rodrigo Aguayo-Ortiz Ellen E Cho Marsha P Pribadi Michael P Dalton Nishadh Rathod M Joanne Lemieux L Michel Espinoza-Fonseca Seth L Robia Aleksey V Zima Howard S Young |
| author_sort | M'Lynn E Fisher |
| collection | DOAJ |
| description | The sarco-plasmic reticulum calcium pump (SERCA) plays a critical role in the contraction-relaxation cycle of muscle. In cardiac muscle, SERCA is regulated by the inhibitor phospholamban. A new regulator, dwarf open reading frame (DWORF), has been reported to displace phospholamban from SERCA. Here, we show that DWORF is a direct activator of SERCA, increasing its turnover rate in the absence of phospholamban. Measurement of in-cell calcium dynamics supports this observation and demonstrates that DWORF increases SERCA-dependent calcium reuptake. These functional observations reveal opposing effects of DWORF activation and phospholamban inhibition of SERCA. To gain mechanistic insight into SERCA activation, fluorescence resonance energy transfer experiments revealed that DWORF has a higher affinity for SERCA in the presence of calcium. Molecular modeling and molecular dynamics simulations provide a model for DWORF activation of SERCA, where DWORF modulates the membrane bilayer and stabilizes the conformations of SERCA that predominate during elevated cytosolic calcium. |
| first_indexed | 2024-04-11T09:05:02Z |
| format | Article |
| id | doaj.art-87991ab8aa184f75a15e117bb6842178 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:05:02Z |
| publishDate | 2021-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-87991ab8aa184f75a15e117bb68421782022-12-22T04:32:39ZengeLife Sciences Publications LtdeLife2050-084X2021-06-011010.7554/eLife.65545Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCAM'Lynn E Fisher0Elisa Bovo1Rodrigo Aguayo-Ortiz2Ellen E Cho3Marsha P Pribadi4Michael P Dalton5https://orcid.org/0000-0001-5296-5099Nishadh Rathod6M Joanne Lemieux7L Michel Espinoza-Fonseca8Seth L Robia9https://orcid.org/0000-0002-1193-9510Aleksey V Zima10Howard S Young11https://orcid.org/0000-0002-5990-8422Department of Biochemistry, University of Alberta, Edmonton, CanadaDepartment of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, United StatesCenter for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, United StatesDepartment of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, United StatesDepartment of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, United StatesDepartment of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, United StatesDepartment of Biochemistry, University of Alberta, Edmonton, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, CanadaCenter for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, United StatesDepartment of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, United StatesDepartment of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, United StatesDepartment of Biochemistry, University of Alberta, Edmonton, CanadaThe sarco-plasmic reticulum calcium pump (SERCA) plays a critical role in the contraction-relaxation cycle of muscle. In cardiac muscle, SERCA is regulated by the inhibitor phospholamban. A new regulator, dwarf open reading frame (DWORF), has been reported to displace phospholamban from SERCA. Here, we show that DWORF is a direct activator of SERCA, increasing its turnover rate in the absence of phospholamban. Measurement of in-cell calcium dynamics supports this observation and demonstrates that DWORF increases SERCA-dependent calcium reuptake. These functional observations reveal opposing effects of DWORF activation and phospholamban inhibition of SERCA. To gain mechanistic insight into SERCA activation, fluorescence resonance energy transfer experiments revealed that DWORF has a higher affinity for SERCA in the presence of calcium. Molecular modeling and molecular dynamics simulations provide a model for DWORF activation of SERCA, where DWORF modulates the membrane bilayer and stabilizes the conformations of SERCA that predominate during elevated cytosolic calcium.https://elifesciences.org/articles/65545calcium ATPasemembrane reconstitutioncellular calcium dynamicsfluorescence resonance energy transfermolecular dynamics simulations |
| spellingShingle | M'Lynn E Fisher Elisa Bovo Rodrigo Aguayo-Ortiz Ellen E Cho Marsha P Pribadi Michael P Dalton Nishadh Rathod M Joanne Lemieux L Michel Espinoza-Fonseca Seth L Robia Aleksey V Zima Howard S Young Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA eLife calcium ATPase membrane reconstitution cellular calcium dynamics fluorescence resonance energy transfer molecular dynamics simulations |
| title | Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA |
| title_full | Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA |
| title_fullStr | Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA |
| title_full_unstemmed | Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA |
| title_short | Dwarf open reading frame (DWORF) is a direct activator of the sarcoplasmic reticulum calcium pump SERCA |
| title_sort | dwarf open reading frame dworf is a direct activator of the sarcoplasmic reticulum calcium pump serca |
| topic | calcium ATPase membrane reconstitution cellular calcium dynamics fluorescence resonance energy transfer molecular dynamics simulations |
| url | https://elifesciences.org/articles/65545 |
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