Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits
The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/16/8891 |
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| author | Nishadh Rathod Jessi J. Bak Joseph O. Primeau M’Lynn E. Fisher Lennane Michel Espinoza-Fonseca Mary Joanne Lemieux Howard S. Young |
| author_facet | Nishadh Rathod Jessi J. Bak Joseph O. Primeau M’Lynn E. Fisher Lennane Michel Espinoza-Fonseca Mary Joanne Lemieux Howard S. Young |
| author_sort | Nishadh Rathod |
| collection | DOAJ |
| description | The sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the “regulins”. Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA—formed by transmembrane helices M2, M6, and M9—can result in distinct functional outcomes. |
| first_indexed | 2024-03-10T08:43:34Z |
| format | Article |
| id | doaj.art-13b74f511ec647bf913c3f3b653074f4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:43:34Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-13b74f511ec647bf913c3f3b653074f42023-11-22T08:02:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216889110.3390/ijms22168891Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory SubunitsNishadh Rathod0Jessi J. Bak1Joseph O. Primeau2M’Lynn E. Fisher3Lennane Michel Espinoza-Fonseca4Mary Joanne Lemieux5Howard S. Young6Department of Biochemistry, University of Alberta, Edmonton, AL T6G 2H7, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, AL T6G 2H7, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, AL T6G 2H7, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, AL T6G 2H7, CanadaCenter for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USADepartment of Biochemistry, University of Alberta, Edmonton, AL T6G 2H7, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, AL T6G 2H7, CanadaThe sarco-endoplasmic reticulum calcium ATPase (SERCA) is responsible for maintaining calcium homeostasis in all eukaryotic cells by actively transporting calcium from the cytosol into the sarco-endoplasmic reticulum (SR/ER) lumen. Calcium is an important signaling ion, and the activity of SERCA is critical for a variety of cellular processes such as muscle contraction, neuronal activity, and energy metabolism. SERCA is regulated by several small transmembrane peptide subunits that are collectively known as the “regulins”. Phospholamban (PLN) and sarcolipin (SLN) are the original and most extensively studied members of the regulin family. PLN and SLN inhibit the calcium transport properties of SERCA and they are required for the proper functioning of cardiac and skeletal muscles, respectively. Myoregulin (MLN), dwarf open reading frame (DWORF), endoregulin (ELN), and another-regulin (ALN) are newly discovered tissue-specific regulators of SERCA. Herein, we compare the functional properties of the regulin family of SERCA transmembrane peptide subunits and consider their regulatory mechanisms in the context of the physiological and pathophysiological roles of these peptides. We present new functional data for human MLN, ELN, and ALN, demonstrating that they are inhibitors of SERCA with distinct functional consequences. Molecular modeling and molecular dynamics simulations of SERCA in complex with the transmembrane domains of MLN and ALN provide insights into how differential binding to the so-called inhibitory groove of SERCA—formed by transmembrane helices M2, M6, and M9—can result in distinct functional outcomes.https://www.mdpi.com/1422-0067/22/16/8891calcium transportsarco-endoplasmic reticulumSERCAphospholambansarcolipinDWORF |
| spellingShingle | Nishadh Rathod Jessi J. Bak Joseph O. Primeau M’Lynn E. Fisher Lennane Michel Espinoza-Fonseca Mary Joanne Lemieux Howard S. Young Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits International Journal of Molecular Sciences calcium transport sarco-endoplasmic reticulum SERCA phospholamban sarcolipin DWORF |
| title | Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits |
| title_full | Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits |
| title_fullStr | Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits |
| title_full_unstemmed | Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits |
| title_short | Nothing Regular about the Regulins: Distinct Functional Properties of SERCA Transmembrane Peptide Regulatory Subunits |
| title_sort | nothing regular about the regulins distinct functional properties of serca transmembrane peptide regulatory subunits |
| topic | calcium transport sarco-endoplasmic reticulum SERCA phospholamban sarcolipin DWORF |
| url | https://www.mdpi.com/1422-0067/22/16/8891 |
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