A galaxy of folds

Abstract

Many protein classification systems capture homologous relationships by grouping domains into families and superfamilies on the basis of sequence similarity. Superfamilies with similar 3D structures are further grouped into folds. In the absence of discernable sequence similarity, these structural similarities were long thought to have originated independently, by convergent evolution. However, the growth of databases and advances in sequence comparison methods have led to the discovery of many distant evolutionary relationships that transcend the boundaries of superfamilies and folds. To investigate the contributions of convergent versus divergent evolution in the origin of protein folds, we clustered representative domains of known structure by their sequence similarity, treating them as point masses in a virtual 2D space which attract or repel each other depending on their pairwise sequence similarities. As expected, families in the same superfamily form tight clusters. But often, superfamilies of the same fold are linked with each other, suggesting that the entire fold evolved from an ancient prototype. Strikingly, some links connect superfamilies with different folds. They arise from modular peptide fragments of between 20 and 40 residues that co-occur in the connected folds in disparate structural contexts. These may be descendants of an ancestral pool of peptide modules that evolved as cofactors in the RNA world and from which the first folded proteins arose by amplification and recombination. Our galaxy of folds summarizes, in a single image, most known and many yet undescribed homologous relationships between protein superfamilies, providing new insights into the evolution of protein domains.

Evolutionary history of redox metal-binding domains across the tree of life

“…An explanation for this result may be that the transition-metal redox domains evolved from short sequences (i.e., modules) that were able to bind transition metals and were later recruited into oxidoreductases, where they assumed a new role in mediating electron transfer reactions. This hypothesis is supported by the observation that an ancestral pool of peptide modules gave rise to the ancient folds (2). To further test our inference, we asked whether these types of transitions are found in available metagenome data.…”

“…Paths that ended with heme-binding domain sequences contained an average of 13.2 steps and 1.5 indels per path (Tables S3 and S4). It seems that protein sequences found in nature are constrained to a very limited portion (∼10 12 ) of all available protein space (10 390 ) (2). For the modules identified here, only a small fraction (10 8 ) of the available protein space was accessed (SI Methods).…”

“…It has been suggested that an ancestral pool of peptide modules may have given rise to the first protein folds that were dispersed into different superfamilies (2)(3)(4). Some of these peptide modules are part of the limited set of building blocks (i.e., the "redox enzyme construction kit") that gave rise to many oxidoreductases (5).…”

“…HMMs (10) are a class of probabilistic models generally applicable to linear sequences (13). Because profile HMMs capture family-specific information, including functionally and structurally important residues, they are more sensitive and accurate than sequence alignments alone when searching for deeply diverged family members (2,14,15). The evolutionary relationships of protein families identified using profile HMMs may be reconstructed with similarity networks.…”

“…By incorporating different metrics (e.g., pairwise alignment of profiles or sequence-to-profile alignments), network analysis provides a flexible approach to access the composition of domains in ancient protein families. In this study we applied a flexible network approach (11,12) and permissive profile alignments (2,14,15) on microbial genome data to reconstruct the evolutionary history of oxidoreductase metal-binding domains. Our results suggest that whereas there were at least 10 independent origins of redox domain families one core family of iron-containing oxidoreductases came to dominate the electron fluxes across the planet before the evolution of oxygen.…”