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Mentor: Ernesto Fuentes, PhD
Year Entered Into Program: 2006
PhD Institution: University of Iowa, 2011
T-cell lymphoma Invasion and Metastasis 1 (Tiam1) protein
is a Guanine Exchange Factor (GEF) that specifically activates the Rho-family
GTPase Rac1. In mammalian cells, spacial and temporal regulation is achieved
via several distinct protein-protein interaction domains. The Fuentes Lab
applies biophysical techniques to understand how each of these domains
contribute to Tiaim1 activity. Included in this set of domains is a Ras Binding
(RB) domain just N-terminal to a Post-synaptic density-95/Discs large/Zonula
occludens-1 (PDZ) domain. Tiam1 GEF activity is thought to increase upon
activated Ras binding to the RB domain, while the functional importance of the
PDZ domain remains a mystery. My research is directed at understanding the
structural and functional relationship between these two domains both alone and
in the context of the full length Tiam1. To understand these domains further,
we express each domain separately and together with various surrounding
domains. The structure of the PDZ domain was solved in both free form and bound
to model peptide ligand. Nuclear magnetic resonance was used to check the
binding affinity of the ligand and to investigate intermolecular dynamics upon
peptide binding. Further structure and function work will be carried out on
neighboring domains in the Tiam1 protein. We are also examining the effect of
mutations in the binding pocket of the PDZ domain contained within the
full-length Tiam1 in vivo.
Clark, B.K., Rosa, E.R., Hall, A.D.,
Shepherd, T.R.:Dynamics of an
Electronic Impact. Oscillator. Phys. Lett. A. 318, 514-521, 2003.
Shepherd, T.R., Klaus, S.M., Liu, X., Ramaswamy,
S., DeMali, K.A., and Fuentes, E.J. (2010). The Tiam1 PDZ Domain Couples to
Syndecan1 and Promotes Cell-Matrix Adhesion, J. Mol. Biol.
Shepherd, T.R. and Fuentes, E.J.:Structural and Thermodynamic Analysis of PDZ/ Ligand Interactions.
Methods in Enzymology, In
T.R., Hard, R.L., Murray, A.M., Pei, D., Fuentes, E.J. (2010).
Distinct Ligand Specificity of the Tiam1 and Tiam2 PDZ Domains.
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