Evolution, folding, and design of TIM barrels and related proteins

Abstract

Proteins are chief actors in life that perform a myriad of exquisite functions. This diversity has been enabled through the evolution and diversification of protein folds. Analysis of sequences and structures strongly suggest that numerous protein pieces have been reused as building blocks and propagated to many modern folds. This information can be traced to understand how the protein world has diversified. In this review, we discuss the latest advances in the analysis of protein evolutionary units, and we use as a model system one of the most abundant and versatile topologies, the TIM-barrel fold, to highlight the existing common principles that interconnect protein evolution, structure, folding, function, and design.

Figure 1

Schematic overview of the relationships between protein fold evolution, experimental characterization, and design approaches discussed in this review. The upper part of the figure shows how evolutionary units are reused through different molecular mechanisms to diversify protein folds. Experimental reconstruction of different evolutionary pathways and the analysis of folding, function, and fitness determinants in evolution increase our knowledge of the protein-based world and allow navigating from Nature to protein design as shown in the bottom part.

Figure 2

Current subdomain classification approaches. Shown is the generation of available subdomain databases including the different input, data processing, and final output. While Fragment/Themes are continuous sequences and are defined by HMM-profile comparisons and structural alignments, TERMs are non-continuous and focus on contact maps for classification. In contrast, EFLs combine information from structure, sequence and function, but are limited by existing annotation of functional sites.

Figure 3

Summary of recent central studies that interconnect the evolution, its experimental reconstruction, folding, and design of TIM-barrel proteins as discussed in this review.