Most brain functions require communication between neurons that is mediated by signaling molecules. G-protein-coupled receptors (GPCRs) are important signaling molecules for most cellular processes. GPCRs are currently the targets for approximately 50% of all drugs in the pharmaceutical industry. Adhesion-type GPCRs are important signaling molecules in the brain and potential treatment of various brain diseases may be possible by better understanding how these receptors function. A major aim of our laboratory is to reveal the mechanism by which adhesion GPCRs function using a combination of structural, biochemical and functional approaches.
With 33 members in humans adhesion GPCRs are the second largest family in the GPCR superfamily.
Recent studies indicate emerging physiological and pathological roles in brain development, bilateral frontoparietal polymicrogyria (BFPP, a brain disorder), synapse formation/maintenance, myelination of neurons, central nervous system angiogenesis, autism, attention deficit/hyperactivity disorder and cell polarity in neural development as well as numerous other diseases including cancer.
Similar to conventional GPCRs, they have seven-pass transmembrane helices.
Unlike conventional GPCRs, they have very large extracellular regions decorated with numerous adhesion domains.
All adhesion-GPCRs have a GAIN domain and most are autoproteolysed within the GAIN domain.
What is GAIN Domain?
The GPCR Autoproteolysis-INducing (GAIN) Domain is an evolutionarily conserved, novel fold that has been recently discovered by our laboratory.
- It is the only extracellular domain shared by all human adhesion GPCRs (except GPR123) and all Polycystic Kidney Disease-1 protein families.
- It is required and sufficient for autoproteolysis.
- It is in close association with the signaling transmembrane helices and may regulate receptor signaling.
- It is a potential drug target.
Since almost nothing is known about this new family of signaling molecules, there are numerous areas that need to be investigated to get a comprehensive understanding of aGPCR function. Our studies focus on different structural elements of the aGPCRs:
- Revealing the role of the GAIN domain in receptor function and understanding its mechanism of action to regulate receptor signaling. These results may have an enormous impact on the design of new drugs against GPCRs.
- Characterizing other extracellular regions of aGPCRs, discovering their binding partners and understanding the effect of ligand binding on receptor signaling.
- Investigating the three-dimensional structure of the transmembrane region of aGPCRs and revealing the interplay between the extracellular domains and the transmembrane region to better understand how the receptor function can be regulated.
We use a combination of x-ray crystallography, eukaryotic expression of recombinant proteins, biophysical methods, biochemical assays and functional methods to address these questions.