Rachelle Gaudet, PhD
Professor
Department of Molecular and Cellular Biology, Faculty of Arts and Sciences
Structural biology of ion channels and transporters
X-ray crystallography and other biophysical and biochemical techniques are applied to study the stereochemistry of signaling and transport through biological membranes. Research interests include the studies of Transient Receptor Potential (TRP) channels, transporters associated with antigen
Commercial Opportunities
X-ray crystallography and other stereochemistry techniques provide valuable tools for structure-based drug development. The Gaudet Laboratory’s main focus is to elucidate gating mechanism of Transient Receptor Potential, TRP, ion channels that are involved in temperature sensing. These studies are of particular importance because biophysical and biochemical mechanisms of pain and heat sensing are of great medical and pharmacological interest. With better understanding of the structures of these TRP channels, one will be equipped to design chemical inhibitors, which could potentially be used therapeutically.
Research focused on ABC transporter associated with antigen processing could be of potential interest for understanding immunity and vaccine development.
TRPV1 - heat receptor for pain:
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This illustration is a surface representation of the TRPV1ankyrin repeat structure (in green) with a bound ATP molecule (multicolor sticks) on a background of capsaicin-laden red pepper flakes. Research from the Gaudet lab addresses the molecular mechanisms for regulating the heat receptor sensitivity. See Lishko et al, 2007, Neuron 54(6):905-18 for more details.
Current Research Interests
- Elucidate the gating mechanism of Transient receptor potential (TRP) ion channels involved in temperature sensing.
- Investigate how Transporter Associated with Antigen Processing, TAP, transports antibody peptides for loading onto MHC class I molecules.
- Explore Nramps (natural resistance-associated macrophage proteins) and the process that allow the proton-driven import of divalent metal ions into cells.
Research Expertise
The Gaudet laboratory uses a combination of x-ray crystallography and other biophysical and biochemical techniques to study the stereochemistry of signaling and transport through biological membranes. Their main focus is the structural study of Transient Receptor Potential (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. They focus on the temperature-sensing TRP channels such as TRPV1, TRPV2, and TRPM8. Several temperature-sensing TRP channels like TRPV1, TRPV2 and TRPA1 are expressed in nociceptor neurons, and therefore responsible for pain sensations in response to noxious stimuli.
The ABC transporter associated with antigen processing, TAP, is another focus of investigation in the Gaudet laboratory. 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, they have developed a model of how ATP binding and hydrolysis fuels peptide transport. More recently, they are tackling questions regarding substrate selectivity and the coupling between ATP hydrolysis, peptide binding and transport.
The Gaudet laboratory is also interested in understanding how metals such as iron and manganese, which are essential to physiological processes such as oxygen transport and energy metabolism, are transported into cells. Nramps (natural resistance-associated macrophage proteins) are transporters that allow the proton-driven import of divalent metal ions into cells. Humans have two Nramp homologs. Nramp1 transports metals across the phagolysosomal membrane of macrophages and other phagocytic cells, and is important for the antimicrobial function of these cells. DMT1 (divalent metal transporter 1, also known as Nramp2 or DCT1) is responsible for absorption of dietary iron and manganese in the proximal duodenum. Furthermore, DMT1 allows assimilation of transferrin-bound iron by the red blood cell precursors in specialized endosomal compartments. The current structural studies of a bacterial Nramp protein, MntH, in the laboratory will allow to determine the molecular mechanism of metal-ion transport by the Nramp family of proteins.
Recently, in collaboration with the laboratory of David Corey, the Gaudet laboratory has undertaken structural studies of the hair cell tip link proteins cadherin-23 and protocadherin-15 that are important in the mechanotransduction process of hearing.