北京大学定量生物学中心
学术报告
题目: Mechanical Activation of Adhesion GPCRs: Emerging Principles from Single-Molecule and Single-Cell Studies
报告人: Professor Jie Yan
Department of Physics and Mechanobiology Institute, National University of Singapore
时间: 12月29日（周一）13:00-14:00
地点: 吕志和楼B101
主持人: 齐志&宋晨
摘要:
Mechanical forces are fundamental regulators of cell polarity, migration, differentiation, and tissue morphogenesis. Adhesion G protein–coupled receptors (aGPCRs) constitute a structurally distinct GPCR family that detects and converts mechanical cues into intracellular signaling, yet the molecular basis of their mechanotransduction has remained incompletely defined. Recent single-molecule and live-cell studies now reveal unifying mechanical principles that span multiple aGPCR subfamilies.
In this seminar, I will present three complementary lines of work that together establish the physiological force ranges, activation modes, and ligand mechanics that govern aGPCR function.
First, using magnetic tweezers, we quantified the mechanical responses of the GAIN domains from several aGPCRs—including GPR56/ADGRG1, latrophilin-1/ADGRL1, BAI3/ADGRB3, and CD97/ADGRE5. Despite belonging to distinct subfamilies, these GAIN domains exhibit remarkably similar behaviors: force-dependent conformational changes, subdomain B destabilization, and Stachel exposure occurring over a narrow range from a few piconewtons to <20 pN. This defines the effective force threshold required for aGPCR activation.
Second, live-cell experiments show that migrating cells naturally generate ~18 pN on GPR56 at retracting fibers. Simultaneous TIRF imaging of G-protein recruitment reveals graded mechanotransduction, where lower forces support non-dissociative signaling and higher forces induce GAIN dissociation and maximal activation. These findings demonstrate that a single aGPCR can operate in multiple mechanical modes depending on load magnitude.
Third, we examine how CD97 transmits force through its ligand CD55, which forms a mechanically weak but rapidly rebinding interaction. Although the CD97–CD55 bond has lifetimes of only seconds at <5 pN, engineered single-chain constructs reveal that rapid rebinding generates a critical force that increases as receptor–ligand spacing decreases. Modeling suggests that in intercellular junctions, where CD97–CD55 pairs cluster at ~20 nm spacing, these interactions can transmit sufficient tension to destabilize GAIN subdomain B, enabling activation.
Together, these studies establish shared biophysical principles underlying aGPCR mechanotransduction and reveal how force magnitude, domain mechanics, and ligand rebinding cooperate to regulate aGPCR signaling across physiological contexts.
报告人简介：
Dr. Yan Jie is a single-molecule biophysicist. He obtained his PhD from the University of Illinois at Chicago in 2005. He is currently a Full Professor in the department of physics and a Principal Investigator in the Mechanobiology Institute at the National University of Singapore, where he leads research in single-molecule studies of the micromechanics of DNA and proteins. His ultimate goal is to understand how force-bearing proteins in cells are able to sense and respond to mechanical forces, and how they can be targeted through pharmaceutical means. He has been recognized for his contributions to the field, being elected as a Fellow of the American Physical Society and a Singapore NRF Investigator, and has published over 130 papers and received two patents.
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