Fan Lab
Location and Contact Information
- Office Phone 212-342-0115
Principal Investigator
Our Research
Our laboratory studies the molecular mechanisms by which class C G protein-coupled receptors (GPCRs) transmit signals across biological membranes. Specifically, we focus on human GABA(B) receptor and human calcium-sensing (CaS) receptor. Both receptors are characterized by a large ligand-binding extracellular domain in addition to the canonical seven-helix transmembrane domain. Another unique feature of these receptors is that they require dimerization for function.
Human GABA(B) receptor mediates inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of GBR1 and GBR2 subunits. We recently solved a near full-length structure of GABA(B) receptor, captured in the inactive state by cryo-electron microscopy. Our structure revealed a novel heterodimer interface between the transmembrane (TM) helices 3 and 5 of both GABA(B) subunits. This interface embodies the signature of GABA(B) receptor’s inactive conformation. Furthermore, we identified a unique intersubunit latch motif within this TM interface that maintains the inactive state of the receptor. Its disruption through mutation results in constitutive receptor activity. We also discovered multiple ligands pre-associated with the receptor, including two large endogenous phospholipids embedded within the TM domains to modulate receptor function and maintain receptor integrity.
Human CaS receptor maintains a stable blood Ca(2+) level through the regulation of parathyroid hormone secretion. We solved the crystal structures of the entire extracellular domain of CaS receptor in the resting and active conformations. We provided direct evidence that L-amino acids are agonists of the receptor. Using anomalous difference maps, we identified multiple novel binding sites for Ca(2+) and PO4(3-). Ca(2+) fulfills two functional roles. First, it maintains the structural integrity of CaS receptor. Second, it is directly involved in receptor activation as it facilitates the formation of a homodimer interface that is unique to the active state. Our results indicate that amino acids and Ca(2+) are co-agonists of CaS receptor, acting jointly to trigger receptor activation. PO4(3-) is also important for structural integrity of the receptor, but it inhibits receptor activity. Therefore, activation of CaS receptor involves an intricate interplay of amino acids, Ca(2+), and PO4(3-).
About Dr. Fan
Dr. Qing R. Fan is a Professor of Pharmacology and Pathology at Columbia University. She obtained her bachelor, master and doctoral degrees from Harvard University. Her graduate thesis was completed in the laboratory of late Professor Don C. Wiley. She carried out her postdoctoral training under the guidance of Professor Wayne A. Hendrickson at Columbia University. Research in her group focuses on the structural studies of G-protein-coupled receptor, with the goal of understanding the ligand-dependent activation mechanisms of these receptors. She was a Pew Scholar in Biomedical Sciences, McKnight Scholar in Neuroscience, Irma T. Hirschl Career Scientist and Schaefer Research Scholar.
Lab Members
Select Publications
Zuo, H., Park, J., Frangaj, A., Ye, J., Lu, G., Manning, J.J., Asher, W.B., Lu, Z., Hu, G., Wang, L., Mendez, J., Eng, E., Zhang, Z., Lin, X., Grasucci, R., Hendrickson, W.A., Clarke, O.B., Javitch, J.A., Conigrave, A.D., and Fan, Q.R. Promiscuous G-protein activation by the calcium-sensing receptor. Nature 629, 481-488 (2024). PMID: 38632411.
Park, J., Zuo, H., Frangaj, A., Fu, Z., Yen, L.Y., Zhang, Z., Mosyak, L., Slavkovich, V.N., Liu, J., Ray, K.M., Cao, B., Vallese, F., Geng, Y., Chen, S., Grassucci, R., Venkata, P.D., Tan, Y.Z., Eng, E., Lee, Y., Kloss, B., Liu, Z., Hendrickson, W.A., Potter, C.S., Carragher, B., Graziano, J., Conigrave, A.D., Frank, J., Clarke, O.B., and Fan, Q.R. Symmetric activation and modulation of the calcium-sensing receptor. Proc. Natl. Acad. Sci. USA 118, e2115849118 (2021). PMID: 34916296.
Park, J., Fu Z., Frangaj, A., Liu, J., Mosyak, L., Shen, T., Slavkovich, V.N., Ray, K.M., Taura, J., Cao, B., Geng, Y., Zuo, H., Kou, Y., Grassucci, R., Chen, S., Liu, Z., Lin, X., Williams, J.P., Rice, W.J., Eng, E.T., Huang, R.K., Soni, R.K., Kloss, B., Yu, Z., Javitch, J.A., Hendrickson, W.A., Slesinger, P.A., Quick, M., Graziano, J., Yu, H., Fiehn, O., Clarke, O.B., Frank, J., Fan, Q.R. Structure of human GABAB receptor in an inactive state. Nature, doi: 10.1038/s41586-020-2452-0 (2020). PMID: 32581365.
Zuo, H., Glaaser, I., Zhao, Y., Kourinov, I., Mosyak, L., Wang, H., Liu, J., Park, J., Frangaj, A., Sturchler, E., Zhou, M., McDonald, P., Geng, Y., Slesinger, P.A. and Fan, Q.R. Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor. Proc. Natl. Acad. Sci. USA. 116, 8370-8379 (2019). PMID: 30971491.
Burmakina, S., Geng, Y., Chen, Y., and Fan, Q.R. Heterodimeric coiled-coil interactions of the human GABAB receptor. Proc. Natl. Acad. Sci. USA. 111, 6958-6963 (2014). PMID: 24778228.
Geng, Y., Mosyak, L., Kurinov, I., Zuo, H., Sturchler, E. Cheng, T.C., Subramanyam, P., Brown, A.P., Brennan, S.C., Mun, H., Bush, M., Chen, Y., Nguyen, T.X., Cao, B., Chang, D.D., Quick, M., Conigrave, A.D., Colecraft, H.M., McDonald, P. and Fan, Q.R. Structural mechanism of ligand activation in human calcium-sensing receptor. eLife. 5, e13662 (2016). PMID: 27434672.
Geng, Y., Bush, M., Mosyak, L., Wang, F., and Fan, Q.R. Structural mechanism of ligand activation in human GABAB receptor. Nature 504, 254-259 (2013). PMID: 24305054.
Geng, Y., Xiong, D., Mosyak, L., Malito, D. L., Kniazeff, J., Chen, Y., Burmakina, S., Quick, M., Bush, M., Javitch, J. A., Pin, J.-P., and Fan, Q.R. Structure and functional interaction of the extracellular domain of human GABAB receptor GBR2. Nature Neuroscience 15, 970-978 (2012). PMID: 22660477.