While the first comparison of the (βα) 8-barrel and flavodoxin-like folds was based on structure similarity, the field of sequence analysis had advanced enormously in the past years with the introduction of profile hidden Markov model (HMM) comparisons. In a follow-up study, the combination of HisF with another member of the flavodoxin-like fold, the nitrite response regulator NarL from Escherichia coli, led to a protein with even higher stability. Based on these findings, it was possible to design a chimeric (βα) 8-barrel through the combination and optimization of parts of imidazole glycerol phosphate synthase (HisF) and the chemotaxis response regulator CheY both from Thermotoga maritima. In an extensive database search, structural similarity between a half-barrel and the flavodoxin-like fold was identified. The (βα) 8-barrel or TIM-barrel fold is one of the most successful scaffolds in evolution. We previously identified one of these α/β fragments. The results suggested that several fragments have been reused throughout evolution and thus appear today in different protein contexts. While they were able to find optimal parameters that successfully separate folds from all-β and α + β classes, this was not the case for the all-α and α/β classes: trying to isolate domains from the same folds inevitably connected domains from other folds. separate island-like network components that encompass structurally similar domains. By varying the thresholds that define a fragment, the authors tried to reproduce the SCOP definition of folds, i.e. represented the protein universe via networks, where the nodes represent domains and the links connected nodes that share a fragment, namely, a sub-domain sized protein segment of similar sequence and structure. The authors found in many instances links between superfamilies of the same fold, and in some cases, between different folds. The distance among points was inversely proportional to their sequence similarity. clustered representative domains by their sequence similarity and represented them in a Cartesian space. ![]() Several recent studies suggest that domains originate from smaller fragments that have been duplicated, recombined, and differentiated. Although domains have thus long been defined as the basic evolutionary unit, , ], their origin itself has been investigated in recent years.Īlthough a de novo assembly of folded proteins or domains by random concatenation of amino acids is not entirely impossible, it is statistically implausible. ![]() To date, SCOP classifies over 290,000 domains according to their architecture and topology into more than 1200 folds that have been previously considered to be evolutionarily unrelated. Significant efforts have been placed on hierarchically classifying domains into categories, such as the CATH, SCOP, and ECOD databases. A basic protein unit is the domain, which is defined as an independently folding unit. In order to be active, most proteins need to assemble into a three-dimensional structure that is encoded by its amino acid sequence. Proteins are critical components in all cellular processes and display an impressive number of diverse functionalities. We believe that our results serve as an invaluable resource for structural and evolutionary biologists and as raw material for the design of custom-made proteins. These data are available in our web server called F(old P)uzzle ( ), which allows to individually filter the dataset and create customized networks for folds of interest. These fragments are present in very different protein environments and represent versatile building blocks for protein design. ![]() ![]() Overall, we found more than 1000 protein fragments of various lengths among different folds through similarity network analysis. To better understand how evolution has shaped our protein universe, we performed an all-against-all comparison of protein domains representing all naturally existing folds and identified conserved homologous protein fragments. The application of these concepts to the design of new proteins using subdomain-sized fragments from different folds has proven to be experimentally successful. Natural evolution has generated an impressively diverse protein universe via duplication and recombination from a set of protein fragments that served as building blocks.
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