From Protein Structure to Function with Bioinformatics.pdf

148 B.H. Dessailly and C.A. Orengoand significantly distinct from other folds (Cuff et al. manuscript in preparation); andindeed, as will be shown presently, fold similarities can provide some clues on functionsimilarities between proteins (Martin et al. 1998).6.2.2 Prediction of Function Using Fold RelationshipsThis section focuses on functional properties that can be inferred using features thatdo not imply homology, i.e. functional properties that tend to arise by convergentevolution; issues regarding functional inference based on homology relationshipsare addressed in Section 6.3 of this chapter.In general, the determination of a protein structure and its fold will allow aresearcher to run a plethora of structure-based function prediction methods thatwould not be available if the structure wasn’t known. Some of these methods relyon the principle that knowing the structure allows one to detect global homologiesthat are not apparent at the sequence level (Lee et al. 2007). But other approachesare only making use of purely structural properties that are expected to be relevantfor a protein to perform its molecular function, with no evolutionary consideration.Many of these methods are covered by several other chapters in this book (seeChapters 7, 8, 10 and 11). Here, only situations that directly relate to knowledgeof the fold are discussed.6.2.2.1 Folds with a Single FunctionA newly solved protein structure can be used to search for fold similarities withpreviously known structures, via structure comparison programs that generallyassess the significance of detected structural similarities using specific scoringschemes. Several of these programs are publicly available and have been recentlybenchmarked using a large dataset of known structure similarities built from CATH(Kolodny et al. 2005; Redfern et al. 2007). Such programs include DALI (Holm andSander 1996a), FATCAT (Ye and Godzik 2004), SSM (Krissinel and Henrick2004), CE (Shindyalov and Bourne 1998) and CATHEDRAL (Redfern et al. 2007).If the new structure is from a protein of unknown function, the next step if foldsimilarity has been detected is to evaluate whether functional annotations can betransferred from structurally similar proteins.Some folds are adopted only by homologous proteins whereas other folds mayhave arisen partly by convergent evolution. These folds are coined homologousand analogous folds, respectively (Moult and Melamud 2000). Similarly, somefolds appear homogeneous in terms of functions whereas others are adopted byproteins with widely divergent functions. It is generally assumed that homologousfolds are more functionally homogeneous than analogous folds (Moult andMelamud 2000). Obviously, if a fold is associated to a unique function X, the recognitionof that fold in a protein of unknown function would directly allow to