Homology Analysis Of (β-α)₈ -barrel Proteins Based On Sequence And Structure Modular Study

The (β-α)₈ barrel structure, which was first observed in triose-phosphate isomerase, is one of the most common folds in nature. Almost all the (β-α)₈ barrel proteins could catalyze reactions, involving in molecular or energy metabolism in cells. Although the similar structures, the amino acid sequences and functions of these proteins show high diversity. Therefore, the study focused on the catalytic function, amino acid sequence and stereo structure of this special fold and the evolution relationships between proteins possessing this structure, could reveal the sequence regular to form certain stereo structure and catalytic function, which will contribute to guide the design of artificial proteins.To explore the possible evolution process of the (β-α)₈ barrel proteins and study the sequence regulation to form this special kind of fold, based on former works, this paper analysed 108 structural and sequencial non-redundant (??)8 barrel proteins systematically, through a novel method combining both structure and sequence information.First, according to the certain structural repetition characteristics, (β-α)₈barrel proteins were splited to structural and sequencial independent fragments (βαandαβ). Then based on the novel ?-first pairwise structural alignment method, combining sequence profile information, form the pairwise similarity score matrix and perform hierarchical cluster forβαandαβfragments respectively. Consequently, 67βαmodules and 54αβmodules were obtained, respectively covering 228βαfragments and 196αβfragments. Each of the modules contains fragments which are similar on both structure and sequence. Minimal modules locate in any position within the whole barrel fold, fromβ-strand 1 toβ-strand 8. Furthermore, common functional characteristics in each modules were analysed. During 121 minimal modules, within 50% of the modules possesses fragments which share common conserved functional sites, such as catalytic sites, metal binding sites, and ligand binding sites. Which could support the homology relationships between fragments in a common module.Moreover, on the basis of minimal modules, the study of the linkage and combination law of minimal modules indicated that some minimal modules could combinate with each other in order to form larger fragments in whole barrel fold. Therefore combination modules were obtained, each of which contains more than one minimal modules. Within 24 out of all the combination modules, fragments have common conserved functional sites. These 24 combination modules appeared in 40 different proteins, and distribute in the whole sequence. At most 7 different proteins share one combination modules.The study result in this paper indicates that the functional and sequencial highly diverse (β-α)₈ barrel proteins could evolve from some basic fragments ofβαorαβstructures through repetition and combination. Basic fragments could combinate with each other to form longer fragments, during which some conserved functional sites may still remain.In addition, this paper also reveal the structural and sequencial regulation to form (β-α)₈ barrel fold, which could be helpful for the (β-α)₈ barrel protein design. From methodological perspective, the combined structure and sequence analysis is a effective approach to explore evolution relationship between sequencial diverse proteins. And whole protein splited analysis method could be applicable to other structural repetition proteins.