Genomic‐scale comparison of sequence‐ and structure‐based methods of function prediction: Does structure provide additional insight?

• Published in: Protein science Vol. 10; no. 5; pp. 1005 - 1014
• Main Authors: Fetrow, Jacquelyn S., Siew, Naomi, Di Gennaro, Jeannine A., Martinez‐Yamout, Maria, Dyson, H. Jane, Skolnick, Jeffrey
• Format: Journal Article
• Language: English
• Published: Bristol Cold Spring Harbor Laboratory Press 01.05.2001
• Subjects: Algorithms; Amino Acid Motifs; Animals; Binding Sites; Caenorhabditis elegans - enzymology; Caenorhabditis elegans - genetics; Circular Dichroism; Computational Biology - methods; Databases as Topic; Disulfide oxidoreductase; fuzzy functional forms (FFFs); Genome, Fungal; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; N33; oligosaccharyltransferase (OST); OST3; OST6; Oxidoreductases - chemistry; Oxidoreductases - genetics; Oxidoreductases - metabolism; Protein Conformation; protein function prediction; Protein Subunits; Quantitative Structure-Activity Relationship; Reproducibility of Results; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae - genetics; Sequence Homology, Amino Acid; structural genomics
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1110/ps.49201

A function annotation method using the sequence‐to‐structure‐to‐function paradigm is applied to the identification of all disulfide oxidoreductases in the Saccharomyces cerevisiae genome. The method identifies 27 sequences as potential disulfide oxidoreductases. All previously known thioredoxins, glutaredoxins, and disulfide isomerases are correctly identified. Three of the 27 predictions are probable false‐positives. Three novel predictions, which subsequently have been experimentally validated, are presented. Two additional novel predictions suggest a disulfide oxidoreductase regulatory mechanism for two subunits (OST3 and OST6) of the yeast oligosaccharyltransferase complex. Based on homology, this prediction can be extended to a potential tumor suppressor gene, N33, in humans, whose biochemical function was not previously known. Attempts to obtain a folded, active N33 construct to test the prediction were unsuccessful. The results show that structure prediction coupled with biochemically relevant structural motifs is a powerful method for the function annotation of genome sequences and can provide more detailed, robust predictions than function prediction methods that rely on sequence comparison alone.