title: New structural and functional contexts of the Dx[DN]xDG linear motif: insights into evolution of calcium-binding proteins.
abstract: Binding of calcium ions (Ca²⁺) to proteins can have profound effects on their structure and function. Common roles of calcium binding include structure stabilization and regulation of activity. It is known that diverse families--EF-hands being one of at least twelve--use a Dx[DN]xDG linear motif to bind calcium in near-identical fashion. Here, four novel structural contexts for the motif are described. Existing experimental data for one of them, a thermophilic archaeal subtilisin, demonstrate for the first time a role for Dx[DN]xDG-bound calcium in protein folding. An integrin-like embedding of the motif in the blade of a β-propeller fold--here named the calcium blade--is discovered in structures of bacterial and fungal proteins. Furthermore, sensitive database searches suggest a common origin for the calcium blade in β-propeller structures of different sizes and a pan-kingdom distribution of these proteins. Factors favouring the multiple convergent evolution of the motif appear to include its general Asp-richness, the regular spacing of the Asp residues and the fact that change of Asp into Gly and vice versa can occur though a single nucleotide change. Among the known structural contexts for the Dx[DN]xDG motif, only the calcium blade and the EF-hand are currently found intracellularly in large numbers, perhaps because the higher extracellular concentration of Ca²⁺ allows for easier fixing of newly evolved motifs that have acquired useful functions. The analysis presented here will inform ongoing efforts toward prediction of similar calcium-binding motifs from sequence information alone.
authors: Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom. drigden@liv.ac.uk
authors: Daniel J
authors: DJ
authors: Rigden
authors: Duncan D
authors: DD
authors: Woodhead
authors: Prudence W H
authors: PW
authors: Wong
authors: Michael Y
authors: MY
authors: Galperin
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D019143:Evolution, Molecular; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
chemical_list: D002135:Calcium-Binding Proteins; D002147:Calmodulin; D002118:Calcium