个人简介

2000 Kaiser Award for Excellence in Teaching 2000 Barany Award for Contributions to Biophysics 1992-1995 Searle Scholar 1991-1996 Rita Allen Scholar 1987-1990 N.I.H. Postdoctoral Fellow, Harvard University

研究领域

Biochemistry

The long-term goal of research in the Komives lab is to understand the parameters that govern protein-protein recognition and the mechanisms by which these interactions contribute to biological function. The relative importance of factors such as hydrophobic effects, electrostatic interactions and dynamics are being defined for several different interactions. These parameters are explored by a combination of molecular biological techniques, protein chemistry, surface plasmon resonance, multidimensional NMR, and mass spectrometry. One project aims to discover how thrombomodulin (TM) converts the pro-coagulant activity of thrombin to anti-coagulant activity. The thrombin-TM interaction involves diffusion-controlled association that is highly electrostatically steered. The binding has no favorable enthalpy change, but is instead driven by entropy. In collaboration with the McCammon group, we have obtained evidence from Accelerated Molecular Dynamics that the TM binding site is dynamically coupled to motions at the thrombin active site. We recently were able to obtain beautiful NMR spectra for thrombin, and are now characterizing its dynamics. A second project in the lab is a joint effort with the G. Ghosh, A. Hoffmann, P. Wolynes and J. Dyson labs. This involves understanding the signal transduction mediated by the family of NFkB transcription factors and their IkB inhibitors. We determined that the binding energy of the complex between IkBa and NFkB (p50/p65) lies at the ends of the binding interface. We showed that IkBa folds upon binding to NFkB and that the fifth and sixth ankyrin repeats are weakly folded according to amide exchange experiments. The weakly-folded parts of IkBa appear to be important for facilitating removal of NFkB from transcription sites and we showed by single molecule FRET that they slowly fluctuate between folded and unfolded states. Taking off on this project, we are now investigating other protein-protein interactions mediated by ankyrin-repeat domain proteins. In particular, we are studying the interaction between ASB9, one member of a large family of E3 ubiquitin ligases, and its target, Creatine Kinase. A third project in the lab is to develop novel proteases for proteomics applications. Starting from alphalytic protease, a particularly stable and highly active protease, we are evolving a family of proteases with unique substrate specificity to expand the protein sequence coverage in proteomics experiments.

近期论文

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Cervantes CF, Bergqvist S, Kjaergaard M, Kroon G, Sue SC, Dyson HJ, Komives EA, "The RelA nuclear localization signal folds upon binding to IκBα.", J Mol Biol, 2011, Vol. 405, Issue 3, 754-64 [View Abstract] DeVries I, Ferreiro DU, Sánchez IE, Komives EA, "Folding kinetics of the cooperatively folded subdomain of the IκBα ankyrin repeat domain.", J Mol Biol, 2011, Vol. 408, Issue 1, 163-76 [View Abstract] Treuheit NA, Beach MA, Komives EA, "Thermodynamic compensation upon binding to exosite 1 and the active site of thrombin.", Biochemistry, 2011, Vol. 50, Issue 21, 4590-6 [View Abstract] Ferreiro DU, Komives EA, "Molecular mechanisms of system control of NF-kappaB signaling by IkappaBalpha.", Biochemistry, 2010, Vol. 49, Issue 8, 1560-7 [View Abstract] Guttman M, Prieto JH, Croy JE, Komives EA, "Decoding of lipoprotein-receptor interactions: properties of ligand binding modules governing interactions with apolipoprotein E.", Biochemistry, 2010, Vol. 49, Issue 6, 1207-16 [View Abstract] Guttman M, Prieto JH, Handel TM, Domaille PJ, Komives EA, "Structure of the minimal interface between ApoE and LRP.", J Mol Biol, 2010, Vol. 398, Issue 2, 306-19 [View Abstract] Bergqvist S, Alverdi V, Mengel B, Hoffmann A, Ghosh G, Komives EA, "Kinetic enhancement of NF-kappaBxDNA dissociation by IkappaBalpha.", Proc Natl Acad Sci U S A, 2009, Vol. 106, Issue 46, 19328-33 [View Abstract] Cervantes CF, Markwick PR, Sue SC, McCammon JA, Dyson HJ, Komives EA, "Functional dynamics of the folded ankyrin repeats of I kappa B alpha revealed by nuclear magnetic resonance.", Biochemistry, 2009, Vol. 48, Issue 33, 8023-31 [View Abstract] Guttman M, Betts GN, Barnes H, Ghassemian M, van der Geer P, Komives EA, "Interactions of the NPXY microdomains of the low density lipoprotein receptor-related protein 1.", Proteomics, 2009, Vol. 9, Issue 22, 5016-28 [View Abstract] Koeppe JR, Beach MA, Baerga-Ortiz A, Kerns SJ, Komives EA, "Mutations in the fourth EGF-like domain affect thrombomodulin-induced changes in the active site of thrombin.", Biochemistry, 2008, Vol. 47, Issue 41, 10933-9 [View Abstract]