Araç Lab
The Araç Lab focuses on understanding how adhesion-class G protein-coupled receptors (aGPCRs) function in the nervous system. They investigate the role of the extracellular region in aGPCR function using biophysical, biochemical, and cell biological methods, along with protein biochemistry and structural biology techniques. Insights gained from these studies inform their research on the physiological and cell biological aspects of aGPCRs. Collaborating with neuroscientists and geneticists, they study aGPCR physiology at the organismal level. Situated at the intersection of biochemistry and neuroscience, their research spans synapse formation, cell adhesion, and the biochemical underpinnings of neurodevelopmental disorders.
Demet Araç
Jorge Alvarado
Jingxian Li
Indya Weathers
Sumit Bandekar
Szymon Kordon
Recent
Conformational coupling between extracellular and transmembrane domains modulates holo-adhesion GPCR function (2024)
Adhesion G Protein-Coupled Receptors (aGPCRs) are key cell-adhesion molecules involved in numerous physiological functions. aGPCRs have large multi-domain extracellular regions (ECRs) containing a conserved GAIN domain that precedes their seven-pass transmembrane domain (7TM). Ligand binding and mechanical force applied on the ECR regulate receptor function. However, how the ECR communicates with the 7TM remains elusive, because the relative orientation and dynamics of the ECR and 7TM within a holoreceptor is unclear. Here, we describe the cryo-EM reconstruction of an aGPCR, Latrophilin3/ADGRL3, and reveal that the GAIN domain adopts a parallel orientation to the transmembrane region and has constrained movement. Single-molecule FRET experiments unveil three slow-exchanging FRET states of the ECR relative to the transmembrane region within the holoreceptor. GAIN-targeted antibodies, and cancer-associated mutations at the GAIN-7TM interface, alter FRET states, cryo-EM conformations, and receptor signaling. Altogether, this data demonstrates conformational and functional coupling between the ECR and 7TM, suggesting an ECR-mediated mechanism for aGPCR activation.
A New Perspective on Adhesion GPCRs Activation Mechanisms (2024)
Adhesion GPCRs are versatile signaling molecules critical for processes like brain development, immunity, and organogenesis. Their recent study define an extracellular region (ECR)-mediated activation mechanism, revealing dynamic receptor regulation beyond the conventional tethered agonist model.