Professor of Molecular and Cellular Biology
Northwest Building, Room 311.13
52 Oxford St
Cambridge, MA 02138
Lab Size: Between 5 and 10
We use a combination of x-ray crystallography, biophysical and biochemical techniques, and functional assays to study the stereochemistry of signaling and transport through biological membranes. We have a particular interest in multidomain proteins and how the individual structure and properties of each domain is integrated to shape the function of the whole protein.
Structural studies of TRP channels
The goal is to elucidate the gating mechanism of TRP ion channels involved in temperature sensing and understand modulatory interactions of proteins and small molecules with TRP channels. We are particularly interested in determining the molecular mechanism of temperature sensing. We therefore focus on the temperature-sensing TRP channels such as TRPV1, and TRPM8. Several temperature-sensing TRP channels are expressed in nociceptor neurons, and therefore responsible for pain sensations in response to noxious stimuli. The biophysical and biochemical mechanisms of pain and heat sensing are therefore not only of academic interest, but also of medical and pharmacological interest. We have determined the structures of several TRPV channel cytosolic domains. We are also using patch-clamp electrophysiology and other functional assays to understand the role of ligand interactions with the cytosolic domains in TRP channel function.
Structural studies of TAP, the transporter associated with antigen processing
The goal is to elucidate how TAP, a heterodimer of two membrane-spanning proteins, TAP1 and TAP2, 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). Through structural and biochemical studies of the cytosolic nucleotide-binding domains of TAP1 and TAP2, we have gained a better understanding of how ATP binding and hydrolysis fuels peptide transport. More recently, we are turning our attention to questions regarding substrate selectivity and the coupling between ATP hydrolysis, peptide binding and transport.
Structural studies of Nramp proteins
Metals like iron and manganese are essential to physiological processes such as oxygen transport and energy metabolism. Nramps (natural resistance-associated macrophage proteins) are transporters that allow the proton-driven import of divalent metals into cells. Humans have two Nramp homologs. Nramp1 transports metals across the phagolysosomal membrane of macrophages and is important for the antimicrobial function of these cells. DMT1 (divalent metal transporter 1 or Nramp2) is responsible for absorption of dietary iron and manganese in the proximal duodenum and assimilation of iron by the red blood cell precursors. The goal of this project is to determine the molecular mechanism of metal-ion transport by the Nramp family of proteins through structural studies of bacterial Nramp proteins.
M. Sotomayor, W. A. Weihofen, R. Gaudet and D. P. Corey (2012) Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction. Nature 492, 128-132. PMCID: PMC3518760
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 140, 541-555. PMCID: PMC3483115
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. PMCID: PMC2948466
E. Procko, M. L. O'Mara, W. F. D. 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.
P. V. Lishko, E. Procko, X. Jin, C. B. Phelps and R. Gaudet (2007) The Ankyrin Repeats of TRPV1 Bind Multiple Ligands and Modulate Channel Sensitivity. Neuron 54, 905-918.