From Protein Structure to Function with Bioinformatics.pdf

188 E.C. Meng et al.Structure-Based Local Environment Search Tool, SCOP: Structural Classificationof Proteins, SOIPPA: Sequence Order-Independent Profile-Profile Alignment,SPASM: SPatial Arrangements of Sidechains and Mainchains, TESS: TEmplateSearch and Superposition8.1 Background and SignificanceThe genomic approach to biology has resulted not only in copious amounts of newsequence and structure data, but also the prospect of obtaining a complete “partslist” for many organisms. However, a parts list is of little use without some understandingof what each part does. Even with entire genome sequences in hand, notall genes have been identified, and among identified genes, significant numbershave not been annotated with any function. The amount of sequence data far outweighsthe available structures, so to a large extent, the assignment of functions(functional annotation) has been performed by large-scale sequence searching andtransferring functional information to the query from any sequences found to besignificantly similar. Many sequence motifs have been identified in characterizedsets of proteins and connected to some aspect of structure or function. However, thereliability and functional specificity of transferred annotations diminish assequences become less similar (Devos and Valencia 2001; Rost 2002). Functionalspecificity refers to the narrowness of an inference; for example, “leucyl aminopeptidase”is more specific than “peptidase.”Protein structures may reveal important similarities or possible evolutionary relationshipsthat are not evident from their sequences alone. Proteins may have divergedso far that their sequences cannot be aligned with confidence, yet retain similar overallstructures, or folds (Chothia and Lesk 1986; Rost 1997). The use of fold similarity forannotation transfer (discussed in Chapter 6), however, shares limitations with the useof sequence similarity: the reliability of annotation transfer between related proteins islower for more distant relationships, and proteins with very similar folds can performdifferent functions (Babbitt and Gerlt 1997; Todd et al. 2001). Therefore, fine-scaledetail and local structure must be considered to accurately describe and predict function.Three-dimensional motifs represent patterns of local structure. Over evolutionarytime, identical proteins can diverge by the accumulation of random neutral changesthat do not change function (neutral drift), but retain structural components critical tothat function. Ideally, a 3D motif will describe exactly these function-critical structuralcomponents and serve as a sensitive and specific signature of the function. A shared3D motif may also reflect convergent evolution between different folds, capturingsimilar arrangements of side chains associated with a similar function. A well-knownexample is the serine protease Asp-His-Ser catalytic triad, used in a mechanisticallysimilar way by structurally dissimilar proteases (see below).Structural genomics initiatives seek to determine the structures of all proteins, inrecognition of the importance of such data for annotation and other applicationssuch as drug development. The magnitude of this task is reduced somewhat by