2023-03-06 ジョージア工科大学
彼らの研究は、約40億年前に進化したタンパク質構造に対して、「クリエイティブデストラクション」をモデルにしており、簡単なタンパク質構造がより複雑な構造を生み出す仕組みを説明する可能性があります。この仕組みは、がんやアルツハイマー病などのタンパク質凝集病の研究にも応用されるかもしれません。
<関連情報>
- https://research.gatech.edu/creative-destruction-williams-lab-probes-evolution-proteins
- https://www.pnas.org/doi/10.1073/pnas.2207897119
創造的破壊:古いタンパク質から新しいタンパク質が折り重なる Creative destruction: New protein folds from old
Claudia Alvarez-Carreño,Rohan J. Gupta,Anton S. Petrov,Loren Dean Williams
Proceedings of the National Academy of Sciences Published:December 19, 2022
DOI:https://doi.org/10.1073/pnas.2207897119
Significance
Mechanisms of emergence and early diversification of structured proteins present deep and difficult problems in evolutionary biology. Here we excavate the deepest evolutionary history, found within the translation machinery, which is an ancient molecular fossil and the birthplace of all proteins. We provide evidence supporting common origins of some of the simplest, oldest, and most common protein folds. The data suggest a mechanism, that we call creative destruction, that explains at molecular level how old folds spawn new folds. In this mechanism, new folds emerge from old folds via gene duplication, protein expression, exploration of new folding landscapes, and adaptation. Creative destruction explains the facile emergence of complex from simple architectures in a funneled exploration.
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.
