From Protein Structure to Function with Bioinformatics.pdf

156 B.H. Dessailly and C.A. OrengoFig. 6.2 Multi-domain architectures of (a) periplasmic glutamate-binding protein from Gramnegativebacteria and (b) subunit NR2 of glutamate [NMDA] receptor from rat. Individualdomains are represented as rectangles. N- and C-termini are represented with capital letters“N” and “C”, respectively. The ligand L-glutamate is represented as a brown sphere. The cellularmembrane in (b) is displayed as a double dotted line. The domains between which L-glutamate binds are coloured green. These domains are homologous to one another, bothwithin and between the two proteins (CATH superfamily 3.40.190.10). These two proteinshave very different functions, as suggested by their very different multi-domain architectures:(a) bacterial periplasmic glutamate-binding protein consists only of the two domains involvedin binding glutamate and freely transports the latter across the periplasm (Takahashi et al.2004). (b) Glutamate [NMDA] receptor (subunit NR2) is part of a transmembrane channel thatplays a major role in excitatory neurotransmission; it consists of five globular domains and itsbinding to L-glutamate participates in opening the channel for cation influx (Furukawa et al.2005). Even though the pair of green domains in these two proteins are homologous and sharethe ability to bind L-glutamate in a similar location of their structure, they undoubtedly havevery different functions6.3.1.2), all members of these superfamilies share a common mechanistic attributein the diverse reactions they catalyse.The SFLD is in fact specifically aimed at describing these mechanisticallydiverse enzyme superfamilies and provides a classification of evolutionarily relatedenzymes notably based on similarities in their functional mechanisms. For example,the SFLD superfamily of haloacid dehalogenases groups together enzymes thatcan process a vast variety of substrates, but always act via the formation of a covalentenzyme-substrate intermediate through a conserved aspartate (Glasner et al.2006), that in turn facilitates cleavage of C-Cl, P-C or P-O bonds. The haloaciddehalogenase superfamily contains 1,285 unique sequences classified in 20 differentfamilies, each of which catalyses a unique reaction (e.g. histidinol phosphatases– EC number 3.1.3.15; or trehalose phosphatases – EC number 3.1.3.12). Some