Professor of Chemistry and Biochemistry
Bruno Zimm Scholar

Office: Natural Sciences Bldg 4324
Phone: 858-534-3058
Email: ekomives@ucsd.edu
Web: komiveslab.ucsd.edu 
Group: View group members

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

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. The favorable entropy of association is probably due to release of water molecules from the interface into the bulk as a large number of amides are completely solvent inaccessible in the interface. When TM binds to thrombin, it appears to transmit conformational changes to the active site loops which we can observe with amide exchange.

A second project in the lab involves the interactions of the LDL-receptor-related protein (LRP-1), which is a 515 kD protein that is responsible for clearing many ligands that are genetically linked to Alzheimers disease. So far, we have been able to narrow-down the binding site of two of these ligands and are solving the NMR structure of the complement repeats that contain the binding sites. For one of the ligands, apolipoprotein E, we were able to define a 20 residue peptide with full LRP-1 binding capacity. This peptide causes chemical shift perturbation within the binding fragment, and we are also solving the structure of the complex. We have also characterized the interaction of the intracellular domain of LRP-1 with signaling molecules such as Shc, cSrc kinase, phospholipase Cg, and several PTN homologs in collaboration with P. van der Geer. We have found that phosphorylation regulates the folded structure of the intracellular domain exposing a secondary interaction site. Proteomics experiments are underway to define which proteins bind to which sites and how binding is dependent on phosphorylation.



A third 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 they slowly fluctuate between folded and unfolded states.

Biophysics
Macromolecular Structure