Identification of family-determining residues in PHD fingers.
Histone modifications are fundamental to chromatin structure and transcriptional regulation, and are recognized by a limited number of protein folds. Among these folds are PHD fingers, which are present in most chromatin modification complexes. To date, about 15 PHD finger domains have been structurally characterized, whereas hundreds of different sequences have been identified. Consequently, an important open problem is to predict structural features of a PHD finger knowing only its sequence. Here, we classify PHD fingers into different groups based on the analysis of residue-residue co-evolution in their sequences. We measure the degree to which fixing the amino acid type at one position modifies the frequencies of amino acids at other positions. We then detect those position/amino acid combinations, or 'conditions', which have the strongest impact on other sequence positions. Clustering these strong conditions yields four families, providing informative labels for PHD finger sequences. Existing experimental results, as well as docking calculations performed here, reveal that these families indeed show discrepancies at the functional level. Our method should facilitate the functional characterization of new PHD fingers, as well as other protein families, solely based on sequence information.
Institute for Computational Medicine and Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA. pslama@cis.jhu.edu
Patrick
P
Slama
Donald
D
Geman
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids; D016000:Cluster Analysis; D019277:Entropy; D019143:Evolution, Molecular; D006657:Histones / Q000737:chemistry; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000145:classification
D000596:Amino Acids; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1