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Mentor: Ernesto Fuentes, PhD
Year Entered Into Program: 2006-2011
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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