Rachelle Gaudet, Ph.D.
Department of Molecular and Cellular Biology, Harvard University
Structural biology of signaling and transport through biological membranes.
We use a combination of x-ray crystallography and other computational, biophysical and biochemical techniques to study the structural mechanisms of signaling and transport through biological membranes. Our research encompasses several protein families: Nramp transporters that use a proton gradient to facilitate the entry of divalent ions (iron and manganese in particular) into cells; non-classical cadherins involved in cellular adhesion and signaling; ABC transporters that use ATP to fuel substrate transport; and TRP channels important to sensing temperature and painful stimuli. We use a variety of cell-based and in vitro biochemical assays, x-ray crystallography, and computational techniques (molecular dynamics simulations and bioinformatics analyses) to discover how these important proteins function in cells.
The TRP channel family is quite diverse. We are interested in 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. Another channel of deep interest to our lab is the TRPV4 channel, a close homolog of TRPV1. Dozens of disease-causing point mutations have been identified in TRPV4, linked to either skeletal dysplasias or neurodegenerative diseases. We are interested in both using the disease information to better understand TRPV4 and in developing mechanistic models of how the mutations cause the diseases.
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 now working on clustered protocadherins involved in the development of the nervous system.
Last but not least, we study Nramp-family transporters of transition metals. NRAMPs are believed to 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 determined a structure of a bacterial NRAMP homolog, and now seek to determine additional structures in other conformational states, as well as use an array of biochemical assays to understand how divalent metals are transported.
Nicoludis JM, Lau SY, Schärfe CP, Marks DS, Weihofen WA, Gaudet R. Structure and Sequence Analyses of Clustered Protocadherins Reveal Antiparallel Interactions that Mediate Homophilic Specificity. Structure. 2015 Nov 3;23(11):2087-98. Epub 2015 Oct 15. PubMed PMID: 26481813; PMCID: PMC4635037.
Grossmann N, Vakkasoglu AS, Hulpke S, Abele R, Gaudet R, Tampé R. Mechanistic determinants of the directionality and energetics of active export by a heterodimeric ABC transporter. Nat Commun. 2014 Nov 7;5:5419. PubMed PMID: 25377891; PMCID: PMC4242082.
Sotomayor M, Weihofen WA, Gaudet R, Corey DP. Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction. Nature. 2012 Dec 6;492(7427):128-32. Epub 2012 Nov 7. PubMed PMID: 23135401; PMCID: PMC3518760.
Lau SY, Procko E, Gaudet R. Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. J Gen Physiol. 2012 Nov;140(5):541-55. PubMed PMID: 23109716; PMCID: PMC3483115.
Northwest lab Bldg., Rm 311.13
Cambridge, MA 02138