Protein Structure and Function. Application of Bioinformatics Methods - John Rigden 2014

Structural Motifs
Background and Significance
What is a Function?

METABOLISM/2.html">THE CONCEPT OF a function can be described at multiple levels and from various Perspectives. Training and testing diverse functional annotation Methods require a unified system for functional Classification. The Gene Ontology (GO) system (Ashburner et al. 2000) provides a hierarchical set of functional descriptors, ranging from broad to specific across three core categories: biological processes, cellular components, and molecular Functions. To describe specific molecular functions of Enzymes, the GO framework incorporates the Enzyme Commission (EC²) classification system, which is also hierarchical: catalyzed reactions are denoted by four-part numbers, where the first digit indicates the broad reaction Class, and the final digit is assigned based on the substrate Specificity of the enzyme. Furthermore, the GO system includes molecular function terms for stable chemical interactions (where substrate binding is not functionally linked to membrane transport or catalytic activity).

Because Structure/135.html">Structural motifs are defined by atomic coordinates, it is most natural to use them to detail molecular functions, such as catalyzing a specific reaction or binding a particular Ligand. However, neither the EC nor the GO provides details regarding enzymatic mechanisms or the specific structural regions responsible for protein function (Babbitt 2003). For instance, two enzymes that catalyze identical overall reactions will share the same EC number, even if their structures and catalytic mechanisms differ significantly. Conversely, enzymes that are clearly homologous and share mechanistic features (such as identical partial reactions) may catalyze entirely different overall reactions, differing across all four EC indices.

² The latest edition was compiled in 1992 by Prof. Webb and the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. Author's note.

In addition to functional classification, structural classifications are frequently employed to train and test annotation methods. The SCOP (Structural Classification of Proteins) database (Murzin et al. 1995) and the CATH (Class, Architecture, Topology, and Homologous superfamily) classification (Orengo et al. 1997) provide hierarchical frameworks for Protein domains—compact structural blocks (Richardson 1981) that appear to have been combined over the course of evolution (Chothia et al. 2003). In the SCOP classification, domains are grouped into families, superfamilies, folds, and classes. Family annotation is often straightforward based solely on sequence data, making it a relatively simple task. The majority of SCOP analysis focuses on identifying superfamily membership. While membership in a particular superfamily offers valuable clues for deciphering protein function, it is not functionally specific. A given structure may perform any of the functions known for other members of the family, or a related function not previously observed within that family. Much like functional classification, structural classification does not provide direct information regarding the specific structural features associated with a given function.