title: Functional recycling of C2 domains throughout evolution: a comparative study of synaptotagmin, protein kinase C and phospholipase C by sequence, structural and modelling approaches.
abstract: The C2 domain is one of the most frequent and widely distributed calcium-binding motifs. Its structure comprises an eight-stranded beta-sandwich with two structural types as if the result of a circular permutation. Combining sequence, structural and modelling information, we have explored, at different levels of granularity, the functional characteristics of several families of C2 domains. At the coarsest level, the similarity correlates with key structural determinants of the C2 domain fold and, at the finest level, with the domain architecture of the proteins containing them, highlighting the functional diversity between the various sub-families. The functional diversity appears as different conserved surface patches throughout this common fold. In some cases, these patches are related to substrate-binding sites whereas in others they correspond to interfaces of presumably permanent interaction between other domains within the same polypeptide chain. For those related to substrate-binding sites, the predictions overlap with biochemical data in addition to providing some novel observations. For those acting as protein-protein interfaces, our modelling analysis suggests that slight variations between families are a result of not only complementary adaptations in the interfaces involved but also different domain architecture. In the light of the sequence and structural genomic projects, the work presented here shows that modelling approaches along with careful sub-typing of protein families will be a powerful combination for a broader coverage in proteomics.
authors.affiliation: Computational Genome Analysis Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. jose.jinenez@cancer.org.uk
authors.forename: José L
authors.initials: JL
authors.lastname: Jiménez
authors.forename: Graham R
authors.initials: GR
authors.lastname: Smith
authors.forename: Bruno
authors.initials: B
authors.lastname: Contreras-Moreira
authors.forename: John G
authors.initials: JG
authors.lastname: Sgouros
authors.forename: Frederic A
authors.initials: FA
authors.lastname: Meunier
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bates
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002135:Calcium-Binding Proteins; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D011485:Protein Binding; D011493:Protein Kinase C / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D040901:Proteomics; D017386:Sequence Homology, Amino Acid; D050857:Synaptotagmins; D010738:Type C Phospholipases / Q000737:chemistry*
chemical_list: D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D050857:Synaptotagmins; D011493:Protein Kinase C; D010738:Type C Phospholipases