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  4. Uncovering and engineering the mechanical properties of the adhesion GPCR ADGRG1 GAIN domain
 
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research article

Uncovering and engineering the mechanical properties of the adhesion GPCR ADGRG1 GAIN domain

Dumas, L.  
•
Marfoglia, M.  
•
Yang, B.
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Key cellular functions depend on the transduction of extracellular mechanical signals by specialized membrane receptors including adhesion G-protein coupled receptors (aGPCRs). While recently solved structures support aGPCR activation through shedding of the extracellular GAIN domain, the molecular mechanisms underpinning receptor mechanosensing remain poorly understood. When probed using single-molecule atomic force spectroscopy and molecular simulations, ADGRG1 GAIN dissociated from its tethered agonist at forces significantly higher than other reported signaling mechanoreceptors. Strong mechanical resistance was achieved through specific structural deformations and force propagation pathways under mechanical load. ADGRG1 GAIN variants computationally designed to lock the alpha and beta subdomains and rewire mechanically-induced structural deformations were found to modulate the GPS-Stachel rupture forces. Our study provides unprecedented insights into the molecular underpinnings of GAIN mechanical stability and paves the way for engineering mechanosensors, better understanding aGPCR function, and informing drug-discovery efforts targeting this important receptor class.

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Type
research article
DOI
10.1101/2023.04.05.535724
Author(s)
Dumas, L.  
•
Marfoglia, M.  
•
Yang, B.
•
Hijazi, M.  
•
Larabi, A.N.  
•
Lau, K.  
•
Pojer, F.  
•
Nash, M.A.
•
Barth, P.  
Date Issued

2023-04-06

Peer reviewed

NON-REVIEWED

Written at

EPFL

EPFL units
UPBARTH  
FunderGrant Number

FNS

514377

Available on Infoscience
April 26, 2023
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/197197
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