Dept of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143-0450, USA
Even when a protein structure is known, it remains a major theoretical and experimental challenge to localize its functional surfaces and understand the role of their constituent residues. One approach is to tease from the evolutionary record those mutation patterns most likely to indicate functionally important sequence positions. The Evolutionary Trace, ET, accomplishes that goal by identifying patterns of residue conservation that correlate with functional divergence within a protein family. On the protein surface, positions where these ET patterns arise form clusters, precisely at binding and catalytic sites.
We will demonstrate evolutionary tracing in SH2 and SH3 modular signaling domains, G protein heterotrimers and DNA binding domains from intracellular hormone receptors. In these proteins, ET can: 1) predict the location of functional interfaces, 2) establish a functional hierarchy among residues within these sites, 3) direct mutagenesis studies of molecular recognition, 4) help model protein quaternary structure, 5) identify unsuspected functional interfaces and unsuspected functions within subgroups of related proteins.
Most generally, ET is a systematic, transparent and novel method that provides an evolutionary perspective on the functional or structural role of residues in a protein structure.
Lichtarge,O. Bourne,H.R. and Cohen,F.E. (1996) J.Mol.Biol. 257:342-358
An Evolutionary Trace Method Defines Surfaces Common to Protein Families.
Lichtarge,O. Bourne,H.R. and Cohen,F.E. (1996) P.N.A.S. in press
Evolutionary Conserved Gabg Binding Surfaces Support a Model of the
G Protein-Receptor Complex.
Lichtarge,O. Yamamoto,K.R. and Cohen,F.E. in preparation
Evolutionary Analysis of the DNA Binding Domain of Intracellular
Transcritption Factors Reveals Novel Interfaces and New Functions.