Comprehensive Repertoire of Foldable Regions within Whole Genomes

In order to get a comprehensive repertoire of foldable domains within whole proteomes, including orphan domains, we developed a novel procedure, called SEG-HCA. From only the information of a single amino acid sequence, SEG-HCA automatically delineates segments possessing high densities in hydrophobic clusters, as defined by Hydrophobic Cluster Analysis (HCA). These hydrophobic clusters mainly correspond to regular secondary structures, which together form structured or foldable regions. Genome-wide analyses revealed that SEG-HCA is opposite of disorder predictors, both addressing distinct structural states. Interestingly, there is however an overlap between the two predictions, including small segments of disordered sequences, which undergo coupled folding and binding. SEG-HCA thus gives access to these specific domains, which are generally poorly represented in domain databases. Comparison of the whole set of SEG-HCA predictions with the Conserved Domain Database (CDD) also highlighted a wide proportion of predicted large (length >50 amino acids) segments, which are CDD orphan. These orphan sequences may either correspond to highly divergent members of already known families or belong to new families of domains. Their comprehensive description thus opens new avenues to investigate new functional and/or structural features, which remained so far uncovered. Altogether, the data described here provide new insights into the protein architecture and organization throughout the three kingdoms of life.Author Summary: Spontaneous or induced folding into a specific 3D structure is a key property of proteins to perform their biological functions. Folded 3D structures of proteins perform specific functions, including interactions with other proteins. Intrinsically disordered regions also mediate interaction, gaining structure only when bound to a target protein. In both cases, hydrophobicity generally plays a major role in the protein segment “foldability”. Here, we developed an original procedure to identify foldable segments from only the information of a single amino acid sequence and to explore protein structures at a proteomic scale. Our approach goes beyond the simple consideration of mean hydrophobicity, by including the secondary structure information through the use of a two-dimensional transposition of the sequence. The developed procedure, combined with disorder predictors, may facilitate the specific identification of small segments that undergo coupled folding and binding. Combined with the analysis of specific domain databases, it also highlights orphan foldable segments, which remain yet uncharacterized.