Predicting specificity-determining residues in two large eukaryotic transcription factor families.
Certain amino acid residues in a protein, when mutated, change the protein's function. We present an improved method of finding these specificity-determining positions that uses all the protein sequence data available for a family of homologous proteins. We study in detail two families of eukaryotic transcription factors, basic leucine zippers and nuclear receptors, because of the large amount of sequences and experimental data available. These protein families also have a clear definition of functional specificity: DNA-binding specificity. We compare our results to three other methods, including the evolutionary trace algorithm and a method that depends on orthology relationships. All of the predictions are compared to the available mutational and crystallographic data. We find that our method provides superior predictions of the known specificity-determining residues and also predicts residue positions within these families that deserve further study for their roles in functional specificity.
Donald
Jason E
JE
Department of Chemistry and Chemical Biology, Harvard University 12 Oxford Street, Cambridge, MA 02138, USA.
Shakhnovich
Eugene I
EI
D000465:Algorithms; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D016350:Leucine Zippers; D009154:Mutation; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics; D020539:Sequence Analysis, Protein / Q000379:methods*; D014157:Transcription Factors / Q000737:chemistry* / Q000145:classification; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011494:Protein Kinases