|
Structural biology, bioinformatics, and computational genomics
The primary goal of our bioinformatics laboratory is to understand how protein functional surfaces control
critical events, such as binding, catalysis and active complex assembly. To address this problem typically requires exhaustive
and expensive mutational analysis in the wetlab. Here instead, we analyze the mutational "experiments" already
performed during evolution and recorded in sequence databases.
Specifically, we have developed a method of sequence analysis that identifies, among divergently related proteins,
patterns of sequence variations that correlate with functional divergence. This evolutionary trace method (ET) ranks
amino acids in a protein by their evolutionary (and presumably functional) importance. As a consequence of this ranking, it
becomes possible to locate functional surfaces on a structure, probe the molecular details of active site function and
specificity, and recognize cryptic functional commonalties in distantly related proteins.
We are using this new approach to probe G protein-mediated signaling, and transcriptional regulation by intracellular
hormone receptors. Our focus in those systems is 1) to model and understand the mechanisms of G protein-coupled receptors; 2)
to characterize interactions between these receptors and the G proteins; and 3) to decipher the origin of recognition
specificity between transcriptional factors and their response elements. In turn, these systems are test beds for
computational tools that can be used broadly to study helical transmembrane receptors, protein-protein interactions and
protein-DNA interactions.
Most generally, we note that genome projects, growing protein structure databases and DNA chip technologies are now
bringing to bear unprecedented amounts of data to fundamental problems in structural biology (protein structure prediction)
and in genomics (gene function prediction). At the same time, these massive data overwhelm conventional means of analysis.
For these reasons, our broad goal is to develop a new generation of bioinformatics methods, such as the evolutionary trace,
that integrate sequence-structure-function data and turn them into new insights in gene expression and protein function.
Selected Publications
Sowa ME, He W, Wensel TG, Lichtarge O (2000) A regulator of G protein signaling interaction surface
linked to effector specificity. Proceedings of the National Academy of Sciences U.S.A. 97:1483-1488.
Sowa ME, He W, Slep KC, Kercher MA, Lichtarge O, Wensel TG (2001) Prediction and confirmation of a site
critical for effector regulation of RGS domain activity. Nature Structural Biology 8:234-237.
Lichtarge O, Sowa ME, Philippi A. (2002) Evolutionary traces of functional surfaces along G protein
signaling pathway. Methods in Enzymology 344:536-556.
Madabushi S, Yao H, Marsh M, Kristensen DM, Philippi A, Sowa ME, Lichtarge O (2002) Structural clusters
of evolutionary trace residues are statistically significant and common in proteins. Journal of Molecular
Biology 316:139-154.
Yao H, Kristensen DM, Mihalek I, Sowa ME, Shaw C, Kimmel M, Kavraki L, Lichtarge O (2003) An accurate,
sensitive, and scalable method to identify functional sites in protein structures. Journal of Molecular
Biology 326:255-261.
Lin CY, Varma MG, Joubel A, Madabushi S, Lichtarge O, Barber DL (2003) Conserved motifs in somatostatin,
D2-dopamine, and alpha 2B-adrenergic receptors for inhibiting the Na-H exchanger, NHE1. Journal of Biological
Chemistry 278:15128-15135.
Mihalek I, Res I, Yao H, Lichtarge O (2003) Combining inference from evolution and geometric probability
in protein structure evaluation. Journal of Molecular Biology 331:263-279.
Madabushi S, Gross AK, Philippi A, Meng EC, Wensel TG, Lichtarge O (2003) Evolutionary trace of
G protein-coupled receptors reveals clusters of residues that determine global and class-specific functions.
Journal of Biological Chemistry 279:8126-8132.
Contact Information
- Olivier Lichtarge, M.D., Ph.D.
- Department of Molecular and Human Genetics
- Baylor College of Medicine
- One Baylor Plaza T921
- Houston, Texas 77030, U.S.A.
- Lab website
- Tel: (713) 798-5646
- Fax: (713) 798-5386
- E-mail: lichtarg@bcm.tmc.edu
|
