Department of Biochemistry
4-403 BSB
Iowa City, IA 52242-1109 USA
phone: 877-846-8569
or 319-335-7932
fax: (319) 335-9570
biochem@uiowa.edu
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Department of Biochemistry
Ernesto Fuentes, PhD
Carver College of Medicine
University of Iowa
51 Newton Rd, 4-632 BSB
Iowa City, IA 52242
Phone: (319) 353-4244
Lab Phone: (319) 7249
Fax: (319) 335-9570
ernesto-fuentes@uiowa.edu
Research Interests
Research in my laboratory will focus on important problems in signal transduction pertinent to human disease. A combination of structural, biochemical, and cell biological approaches will be used to gain insight into the molecular mechanisms governing specific signal transduction pathways. A major goal will be to elucidate the role(s) of structure, energetics, and dynamics involved in these signaling processes.
Two main areas of research are outlined below:
- Previous studies have demonstrated that proteins are highly cooperative with respect to folding and ligand binding. Furthermore, many enzymes display catalytic properties that are regulated allosterically. We are interested in understanding the physical mechanisms responsible for these cooperative and allosteric effects in proteins. Recent studies of PDZ (post-synaptic density-95/discs large/zonula occludens-1) domains using state-of-the-art solution nuclear magnetic resonance (NMR) dynamics experiments suggest that protein dynamics may be one possible mechanism used to propagate signals/energy within a protein molecule, a property known as intramolecular signaling (communication within a protein). (Figure 1). This hypothesis will be further tested by characterizing the backbone and side-chain motions of various single-domain enzymes and signaling domains using NMR techniques coupled with detailed biochemical analysis. Future efforts will exploit intramolecular allostery to identify novel sites in proteins that modulate function, providing a molecular target for novel allosteric inhibitors.
Figure 1. Propagation of dynamics to distal sites in hPTP1E PDZ2. Labeled residues have perturbed side-chain dynamics >7 ? from the peptide ligand. Fuentes et al., JMB (2004)
- Recent work has focused on a class of signaling molecules known as Rho GTPases, a sub-family of the well know Ras GTPases. Like Ras, Rho-family GTPases cycle between active GTP-bound and inactive GDP-bound states. In the active state, Rho GTPases interact with effector proteins that coordinate changes in gene expression and the actin cytoskeleton. Several regulatory molecules such as guanine exchange factors (GEFs) and GTPase activating proteins (GAPs) are critical for regulating the activity of Rho GTPases. The aberrant function of RhoGEFs has been associated with human diseases, including cancer, developmental anomalies, and mental retardation. In addition to the signature catalytic Dbl homology domain (DH domain), GEFs generally contain other signaling domains that contribute to function and/or signaling specificity. Studies in my laboratory will focus on the structural and biochemical features of these auxiliary domains that are critical for the cellular function and disease progression.
Figure 2. The regulatory cycle for Rho-family GTPases.
Recent Publications
Shepherd, T.R., Klaus, S.M., Liu, X., Ramaswamy, S., DeMali, K.A., Fuentes, E.J. (2010) The Tiam PDZ domain couples to Syndecan 1 and promotes cell-matrix adhesion. J Mol Biol. May 21;398(5):730-746. Epub 2010 Mar 31.
Petit, C.M., Zhang, J., Sapienza, P.J., Fuentes, E.J., Lee, A.L. (2009) Hidden dynamic allostery in a PDZ domain. Proc Natl Acad Sci USA, Oct 27;106(43):18249-18254. Epub 2009 Oct 14. Download reprint pdf
Law, A.B., Fuentes, E.J., Lee, A.L. (2009) Conservation of side-chain dynamics within a protein family. J Am Chem Soc. May 13;131(18):6322-6333. Download reprint pdf
Fuentes E.J., Gilmore S.A., Mauldin R.V. and L. Lee A.L. Evaluation of Energetic and Dynamic Coupling Networks in a PDZ Domain Protein. Journal of Molecular Biology 364:337-351 (2006). Download reprint pdf
Tsonis P.A. and Fuentes E.J. Focus on molecules:Pax-6, the eye master. Experimental Eye Research 83:233-234 (2006). Download reprint pdf
Fuentes E.J., Der C.J., and Lee, A.L. Ligand-Dependent Dynamics and intramolecular signaling in a PDZ domain. Journal of Molecular Biology 335:1105-1115 (2004). Download reprint pdf
Fuentes E.J., Karnoub A.E., Booden M.A., Der C.J., and Campbell S.L. Critical role of the pleckstrin homology domain in Dbs signaling and growth regulation. Journal of Biological Chemistry, 278:21188-21196 (2003). Download reprint pdf
Kranz J.K., Flynn P.F., Fuentes E.J., Wand A.J. Dissection of the pathway of molecular recognition by calmodulin. Biochemistry, 41:2599-2608 (2002). Download reprint pdf
Dai Q.H., Tommos C., Fuentes E.J., Blomberg M.R., Dutton P.L., Wand A.J. Structure of a de novo designed protein model of radical enzymes. Journal of the American Chemical Society, 124:10952-10953 (2002). Download reprint pdf
Affiliations
Molecular and Cellular Biology Program
Holden Comprehensive Cancer Center
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