Diversity in αβ and βα Loop Connections in TIM Barrel Proteins: Implications for Stability and Design of the Fold

摘要

The (βα)~(8)/TIM barrel is one of the most common folds of known protein structures facilitating diverse catalytic functions. The fold is formed by the repetition of the basic βαβ building block in which the β-strands are followed by α-helices eight times alternating in sequence and structure. αβ and βα loops connecting α-helices to the β-strands and the β-strands to the α-helices contribute to stability and function, respectively, an inherent imposition by the TIM barrel architecture itself. In this study, αβ and βα loops from a data set of 430 non-redundant, high-resolution triosephosphate isomerase (TIM) barrels bearing sequence homology of <30% were analyzed for their amino acid propensities, sequence profiles, and positional preferences of amino acids. While the distribution of short connections is significantly higher in αβ loops, there appears to be no such preference in βα loops. Glycine, proline, lysine, and arginine tend to show greater preference to occur in αβ loops, whereas serine, threonine, cysteine, tryptophan, and histidine occur more frequently in βα loops. In addition, striking dissimilarities in sequence and positional preferences of amino acids, especially, in short, αβ and βα loops are observed. Together, the analysis suggests the role for short loops and charged residues in promoting both non-polar and polar interactions and in β strand registry. The observed diversity, perhaps, dictates the distinct role of αβ and βα loops in stability and function, respectively. In summary, the overall observations and reasoning, in addition to steering protein engineering efforts on TIM barrel design and stabilization can provide the basis for incorporating consensus loop sequences for designing independently folding βαβ modules.