The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms
Summary: Adhesion G protein-coupled receptors (aGPCRs) are a large GPCR class that direct diverse fundamental biological processes. One prominent mechanism for aGPCR agonism involves autoproteolytic cleavage, which generates an activating, membrane-proximal tethered agonist (TA). How universal this...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723005636 |
| _version_ | 1797820667812380672 |
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| author | Duy Lan Huong Bui Andrew Roach Jingxian Li Sumit J. Bandekar Elizabeth Orput Ritika Raghavan Demet Araç Richard C. Sando |
| author_facet | Duy Lan Huong Bui Andrew Roach Jingxian Li Sumit J. Bandekar Elizabeth Orput Ritika Raghavan Demet Araç Richard C. Sando |
| author_sort | Duy Lan Huong Bui |
| collection | DOAJ |
| description | Summary: Adhesion G protein-coupled receptors (aGPCRs) are a large GPCR class that direct diverse fundamental biological processes. One prominent mechanism for aGPCR agonism involves autoproteolytic cleavage, which generates an activating, membrane-proximal tethered agonist (TA). How universal this mechanism is for all aGPCRs is unclear. Here, we investigate G protein induction principles of aGPCRs using mammalian latrophilin 3 (LPHN3) and cadherin EGF LAG-repeat 7-transmembrane receptors 1–3 (CELSR1–3), members of two aGPCR families conserved from invertebrates to vertebrates. LPHNs and CELSRs mediate fundamental aspects of brain development, yet CELSR signaling mechanisms are unknown. We find that CELSR1 and CELSR3 are cleavage deficient, while CELSR2 is efficiently cleaved. Despite differential autoproteolysis, CELSR1–3 all engage GαS, and CELSR1 or CELSR3 TA point mutants retain GαS coupling activity. CELSR2 autoproteolysis enhances GαS coupling, yet acute TA exposure alone is insufficient. These studies support that aGPCRs signal via multiple paradigms and provide insights into CELSR biological function. |
| first_indexed | 2024-03-13T09:42:35Z |
| format | Article |
| id | doaj.art-8f4a596913f5446cb1c98429a2c5beec |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-13T09:42:35Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-8f4a596913f5446cb1c98429a2c5beec2023-05-25T04:24:17ZengElsevierCell Reports2211-12472023-06-01426112552The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanismsDuy Lan Huong Bui0Andrew Roach1Jingxian Li2Sumit J. Bandekar3Elizabeth Orput4Ritika Raghavan5Demet Araç6Richard C. Sando7Department of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USADepartment of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USADepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USADepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USADepartment of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USADepartment of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USADepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USADepartment of Pharmacology, Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240, USA; Corresponding authorSummary: Adhesion G protein-coupled receptors (aGPCRs) are a large GPCR class that direct diverse fundamental biological processes. One prominent mechanism for aGPCR agonism involves autoproteolytic cleavage, which generates an activating, membrane-proximal tethered agonist (TA). How universal this mechanism is for all aGPCRs is unclear. Here, we investigate G protein induction principles of aGPCRs using mammalian latrophilin 3 (LPHN3) and cadherin EGF LAG-repeat 7-transmembrane receptors 1–3 (CELSR1–3), members of two aGPCR families conserved from invertebrates to vertebrates. LPHNs and CELSRs mediate fundamental aspects of brain development, yet CELSR signaling mechanisms are unknown. We find that CELSR1 and CELSR3 are cleavage deficient, while CELSR2 is efficiently cleaved. Despite differential autoproteolysis, CELSR1–3 all engage GαS, and CELSR1 or CELSR3 TA point mutants retain GαS coupling activity. CELSR2 autoproteolysis enhances GαS coupling, yet acute TA exposure alone is insufficient. These studies support that aGPCRs signal via multiple paradigms and provide insights into CELSR biological function.http://www.sciencedirect.com/science/article/pii/S2211124723005636CP: Cell biology |
| spellingShingle | Duy Lan Huong Bui Andrew Roach Jingxian Li Sumit J. Bandekar Elizabeth Orput Ritika Raghavan Demet Araç Richard C. Sando The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms Cell Reports CP: Cell biology |
| title | The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms |
| title_full | The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms |
| title_fullStr | The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms |
| title_full_unstemmed | The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms |
| title_short | The adhesion GPCRs CELSR1–3 and LPHN3 engage G proteins via distinct activation mechanisms |
| title_sort | adhesion gpcrs celsr1 3 and lphn3 engage g proteins via distinct activation mechanisms |
| topic | CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723005636 |
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