Connecting protein structure with predictions of regulatory sites.
A common task posed by microarray experiments is to infer the binding site preferences for a known transcription factor from a collection of genes that it regulates and to ascertain whether the factor acts alone or in a complex. The converse problem can also be posed: Given a collection of binding sites, can the regulatory factor or complex of factors be inferred? Both tasks are substantially facilitated by using relatively simple homology models for protein-DNA interactions, as well as the rapidly expanding protein structure database. For budding yeast, we are able to construct reliable structural models for 67 transcription factors and with them redetermine factor binding sites by using a Bayesian Gibbs sampling algorithm and an extensive protein localization data set. For 49 factors in common with a prior analysis of this data set (based largely on phylogenetic conservation), we find that half of the previously predicted binding motifs are in need of some revision. We also solve the inverse problem of ascertaining the factors from the binding sites by assigning a correct protein fold to 25 of the 49 cases from a previous study. Our approach is easily extended to other organisms, including higher eukaryotes. Our study highlights the utility of enlarging current structural genomics projects that exhaustively sample fold structure space to include all factors with significantly different DNA-binding specificities.
Morozov
Alexandre V
AV
Center for Studies in Physics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. morozov@edsb.rockefeller.edu
Siggia
Eric D
ED
D000595:Amino Acid Sequence; D001483:Base Sequence; D004271:DNA, Fungal / Q000378:metabolism; D021901:DNA, Intergenic / Q000235:genetics; D019281:Dimerization; D015966:Gene Expression Regulation, Fungal; D018257:Helix-Loop-Helix Motifs; D016350:Leucine Zippers; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012045:Regulatory Sequences, Nucleic Acid; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000378:metabolism
D004271:DNA, Fungal; D021901:DNA, Intergenic; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors