期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：49
DOI：10.1073/pnas.2026165118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Proteins conduct numerous complex biological functions by use of tailored structural dynamics. The molecular details of how these emerged from ancestral peptides remains mysterious. How does nature utilize the same repertoire of folds to diversify function? To shed light on this, we analyzed bilobed proteins with a common structural core, which is spread throughout the tree of life and is involved in diverse biological functions such as transcription, enzymatic catalysis, membrane transport, and signaling. We show here that the structural dynamics of the structural core differentiate predominantly via terminal additions during a long-period evolution. This diversifies substrate specificity and, ultimately, biological function.
Novel biophysical tools allow the structural dynamics of proteins and the regulation of such dynamics by binding partners to be explored in unprecedented detail. Although this has provided critical insights into protein function, the means by which structural dynamics direct protein evolution remain poorly understood. Here, we investigated how proteins with a bilobed structure, composed of two related domains from the periplasmic-binding protein–like II domain family, have undergone divergent evolution, leading to adaptation of their structural dynamics. We performed a structural analysis on ∼600 bilobed proteins with a common primordial structural core, which we complemented with biophysical studies to explore the structural dynamics of selected examples by single-molecule Förster resonance energy transfer and Hydrogen–Deuterium exchange mass spectrometry. We show that evolutionary modifications of the structural core, largely at its termini, enable distinct structural dynamics, allowing the diversification of these proteins into transcription factors, enzymes, and extracytoplasmic transport-related proteins. Structural embellishments of the core created interdomain interactions that stabilized structural states, reshaping the active site geometry, and ultimately altered substrate specificity. Our findings reveal an as-yet-unrecognized mechanism for the emergence of functional promiscuity during long periods of evolution and are applicable to a large number of domain architectures.
关键词：biophysics; evolution; structural dynamics; protein structure; ligand binding
