Structural dynamics in the evolution of a bilobed protein scaffold

Giorgos Gouridis, Yusran A. Muthahari, Marijn de Boer, Douglas A. Griffith, Alexandra Tsirigotaki, Konstantinos Tassis, Niels Zijlstra, Ruixue Xu, Nikolaos Eleftheriadis, Yovin Sugijo, Martin Zacharias, Alexander Domling, Spyridoula Karamanou, Charalambos Pozidis, Anastassios Economou, Thorben Cordes

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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 Forster € 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.

Original languageEnglish
Article numbere2026165118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number49
StatePublished - 7 Dec 2021
Externally publishedYes


  • Biophysics
  • Evolution
  • Ligand binding
  • Protein structure
  • Structural dynamics


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