Creative destruction: New protein folds from old

Abstract

Mechanisms of emergence and divergence of protein folds pose central questions in biological sciences. Incremental mutation and stepwise adaptation explain relationships between topologically similar protein folds. However, the universe of folds is diverse and riotous, suggesting more potent and creative forces are at play. Sequence and structure similarity are observed between distinct folds, indicating that proteins with distinct folds may share common ancestry. We found evidence of common ancestry between three distinct β-barrel folds: Scr kinase family homology (SH3), oligonucleotide/oligosaccharide-binding (OB), and cradle loop barrel (CLB). The data suggest a mechanism of fold evolution that interconverts SH3, OB, and CLB. This mechanism, which we call creative destruction, can be generalized to explain many examples of fold evolution including circular permutation. In creative destruction, an open reading frame duplicates or otherwise merges with another to produce a fused polypeptide. A merger forces two ancestral domains into a new sequence and spatial context. The fused polypeptide can explore folding landscapes that are inaccessible to either of the independent ancestral domains. However, the folding landscapes of the fused polypeptide are not fully independent of those of the ancestral domains. Creative destruction is thus partially conservative; a daughter fold inherits some motifs from ancestral folds. After merger and refolding, adaptive processes such as mutation and loss of extraneous segments optimize the new daughter fold. This model has application in disease states characterized by genetic instability. Fused proteins observed in cancer cells are likely to experience remodeled folding landscapes and realize altered folds, conferring new or altered functions.

Retracing the evolution of a modern periplasmic binding protein

“…The individual parts readily assemble to form a heterodimer, not just when mixing the individually purified lobes, but also within the cell upon coexpression. While the N-and C-terminal lobes appear to be stable and well-behaved proteins on their own, formation of the heterodimer almost completely restores the characteristics of the full-length RBP, confirming the importance of interdomain interactions on the evolution, stability and function of the PBP fold, similarly to what has been reported for other multidomain proteins (Alvarez-Carreño et al, 2022;Han et al, 2007;Vogel et al, 2004).…”

“…It has been previously suggested that this common ancestor could have been a CheY-like protein adopting a flavodoxin-like fold. Formation of an ancestral dimer in combination with a gene duplication and fusion event might have led to the typical bilobal structure of the modern PBP (Figure 1a), an event that has already been investigated for the evolution of other protein folds (Alvarez-Carreño et al, 2022;Farías-Rico et al, 2014;Toledo-Patiño et al, 2019).…”

Fluid protein fold space and its implications

“…Proteins with conserved secondary structures have also been shown to assume different tertiary arrangements. [ 26,75,76 ] Furthermore, new protein folds can evolve by gene fusion in a process known as “creative destruction.” [ 77 ] In this process, a fused polypeptide can combine conserved elements of secondary or supersecondary structure in new ways while the remainders of the ancestral folds are destroyed.…”

Deep Generative Models of Protein Structure Uncover Distant Relationships Across a Continuous Fold Space

“…The transition of a protein sequence from one fold to another, whether it be nearby (A → B) or more distant (A → C), and be it naturally (via evolution) or artificially (via design/engineering), likely occurs over multiple intermediate steps. These mechanistic steps include processes such as combining or permuting short secondary structural segments or longer regions (such as whole secondary structural elements [SSEs]), or mutating individual residues via nonsynonymous substitutions [5,[13][14][15][16]. In general, each such step may yield a new 3D structure, and that structure may correspond to the same or a different 'fold'.…”