Department of Molecular & Cellular Biology
The TRP channel family is quite diverse. We focus on the TRP channels that respond to temperature, including the vanilloid receptor (TRPV1) responding to heat and chili peppers, the cold and menthol receptor (TRPM8), and TRPA1, a noxious cold and pungent compound sensor in humans. Capsaicin, the pungent substance in hot chili peppers, mimics the effects of heat on TRPV1. Therefore, using capsaicin or other activators, as well as inhibitors like capsazepine, structural studies of different closed and open states of the channel are possible. Our overall goal is to elucidate the gating mechanism of TRP channels by temperature and understand modulatory interactions of proteins and small molecules with TRP channels.
Cadherins and protocadherins are important in cellular adhesion and signaling processes. We are interested in the sequence and structural diversity of this large protein family. We have determined structures of cadherin-23 and protocadherin-15, which are important in hearing. We are also working on other protocadherins involved in the development of the nervous system.
In our project on ABC transporters, we are interested in the role of sequence and structural asymmetry in the function of these dimeric proteins. Our main model transporter, TAP, is a heterodimer of two membrane-spanning proteins, TAP1 and TAP2, and transports peptides generated by the proteasome in the cytosol into the endoplasmic reticulum for loading onto MHC class I molecules. Loaded class I molecules then travel to the cell surface and present the peptides to T cells, an immune system mechanism to recognize and eliminate deregulated or tumorigenic cells, virally-infected cells and foreign cells (e.g. graft rejection).
Whereas ABC transporters use ATP to power substrate transport, NRAMPs use a proton gradient to allow divalent metal uptake. NRAMPs are crucial to iron and manganese uptake and homeostasis, and are important in the immune response to intracellular pathogens. We aim to determine the structure of a bacterial NRAMP homolog to understand how divalent metals are transported.
E. Procko, M.L. O'Mara, W.F. Bennett, D.P. Tieleman and R. Gaudet (2009) The mechanism of ABC transporters: general lessons from structural and functional studies of an antigenic peptide transporter. FASEB Journal, 23: 1287-302.
M. Sotomayor, W.A. Weihofen, R. Gaudet and D.P. Corey (2010) Structural Determinants of Cadherin-23 Function in Hearing and Deafness. Neuron, 66: 85-100.
S.Y. Lau, E. Procko and R. Gaudet (2012) Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. Journal of General Physiology (in press).
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