From Protein Structure to Function with Bioinformatics.pdf

144 B.H. Dessailly and C.A. Orengowhereas a biochemist would generally define the function of the protein he studies onthe basis of its molecular interactions or catalytic activity (e.g. “Receptor-interactingserine/threonine-protein kinase”). Because of these different usages of the word, it isvery difficult to provide a universal and widely accepted definition of function.However, it is not essential to come up with such a definition. The GeneOntology (GO) consortium have proposed a framework with which they have beenable to define or, most importantly, categorise the functions of proteins in a widelyaccepted way (The Gene Ontology Consortium 2000). In GO, three differentaspects of function are considered and defined separately. According to GO, thecellular component describes the biological structures to which the protein belongs(e.g. nucleus or ribosome); the biological process corresponds to the processes orpathways in which the protein is involved (e.g. metabolism, signal transduction orcell differentiation); the molecular function of a protein is the ensemble of activitiesit can undertake (e.g. binding, catalysis or transport).Three-dimensional structures of proteins mostly shed light on catalytic mechanismsand potential interactions with other molecules, both aspects which are coveredby the molecular function category. Consequently, it is essentially molecularfunction that is considered when dealing with structure-function relationship as isthe case in this chapter.Several databases and annotation systems are available for the description of themolecular function of proteins (see Table 6.1), and are very helpful for studyingstructure-function relationships, notably on an automated basis. Probably the oldestsystem for describing the molecular function of proteins is the Enzyme Commissionnumbering scheme (EC) in which enzymatic reactions are hierarchically classifiedusing a four-digit system, where each level describes increasingly detailed aspectsof the reaction, from the general type of catalytic activity (oxidoreductase, hydrolase,etc.) to the specific molecule that acts as substrate of the reaction (NomenclatureCommittee of the IUBMB 1992). In order to address long-standing limitations of theEC classification, two new databases have recently been set up to classify enzymesand their reactions: EzCatDB (“Enzyme catalytic-mechanism Database”) (Nagano2005) and MACiE (“Mechanism, Annotation and Classification in Enzymes”)(Holliday et al. 2007). Both of these databases focus on the description and classificationof enzymatic reaction mechanisms rather than the reactions themselves, sinceit has been argued that a reaction-based classification like the EC system is not necessarilyappropriate as a classification of the corresponding enzymes (O’Boyle et al.2007). Complementary to these databases, the Catalytic Site Atlas provides detailedinformation on the specific amino acid residues that directly participate in catalyticmechanisms for enzymes of known structure (Porter et al. 2004). Several databasesprovide further description of all protein residues involved in binding biologicallyimportant molecules such as substrates and cofactors (Lopez et al. 2007; Dessaillyet al. 2008). Other widely-used annotation systems for protein function includeKEGG, which was initially aimed at describing metabolic pathways and biologicalreaction networks, and has now extended into a more widely-scoped classificationsystem of biological functions (Kanehisa et al. 2008); and FUNCAT (the FunctionalCatalogue), which classifies protein functions into a unique hierarchical tree