Piconewton Forces Mediate GAIN Domain Dissociation of the Latrophilin-3 Adhesion GPCR
Latrophilins are adhesion G-protein coupled receptors (aGPCRs) that control excitatory synapse formation. Most aGPCRs, including latrophilins, are autoproteolytically cleaved at their GPCR-autoproteolysis inducing (GAIN) domain, but the two resulting fragments remain noncovalently associated on the cell surface. Force-mediated dissociation of the fragments is thought to activate G-protein signaling, but how this mechanosensitivity arises is poorly understood. Here, we use magnetic tweezer assays to show that physiologically relevant forces in the 1-10 pN range lead to dissociation of the latrophilin-3 GAIN domain on the seconds-to-minutes time scale, compared to days in the absence of force. In addition, we find that the GAIN domain undergoes large changes in length in response to increasing mechanical load. These data are consistent with a model in which a force-sensitive equilibrium between compact and extended GAIN domain states precedes dissociation, suggesting a mechanism by which latrophilins and other aGPCRs may mediate mechanically induced signal transduction.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Nano letters - 23(2023), 20 vom: 25. Okt., Seite 9187-9194 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhong, Brian L [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 26.10.2023 Date Revised 16.03.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Jan 13;:. - PMID 36711622 Citation Status MEDLINE |
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| doi: |
10.1021/acs.nanolett.3c03171 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363248552 |
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| 100 | 1 | |a Zhong, Brian L |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Piconewton Forces Mediate GAIN Domain Dissociation of the Latrophilin-3 Adhesion GPCR |
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| 500 | |a Date Revised 16.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: bioRxiv. 2023 Jan 13;:. - PMID 36711622 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Latrophilins are adhesion G-protein coupled receptors (aGPCRs) that control excitatory synapse formation. Most aGPCRs, including latrophilins, are autoproteolytically cleaved at their GPCR-autoproteolysis inducing (GAIN) domain, but the two resulting fragments remain noncovalently associated on the cell surface. Force-mediated dissociation of the fragments is thought to activate G-protein signaling, but how this mechanosensitivity arises is poorly understood. Here, we use magnetic tweezer assays to show that physiologically relevant forces in the 1-10 pN range lead to dissociation of the latrophilin-3 GAIN domain on the seconds-to-minutes time scale, compared to days in the absence of force. In addition, we find that the GAIN domain undergoes large changes in length in response to increasing mechanical load. These data are consistent with a model in which a force-sensitive equilibrium between compact and extended GAIN domain states precedes dissociation, suggesting a mechanism by which latrophilins and other aGPCRs may mediate mechanically induced signal transduction | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a adhesion GPCR | |
| 650 | 4 | |a force spectroscopy | |
| 650 | 4 | |a latrophilin | |
| 650 | 4 | |a magnetic tweezers | |
| 650 | 4 | |a mechanobiology | |
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| 700 | 1 | |a Lee, Christina E |e verfasserin |4 aut | |
| 700 | 1 | |a Vachharajani, Vipul T |e verfasserin |4 aut | |
| 700 | 1 | |a Bauer, Magnus S |e verfasserin |4 aut | |
| 700 | 1 | |a Südhof, Thomas C |e verfasserin |4 aut | |
| 700 | 1 | |a Dunn, Alexander R |e verfasserin |4 aut | |
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