@article {68299,
	title = {Many sequence-diverse domains switch between alpha-helix and beta-sheet folds},
	journal = {Biophysical Journal},
	volume = {121},
	year = {2022},
	month = {2022 Feb 01},
	pages = {156a},
	abstract = {<p>The protein folding paradigm asserts that the three-dimensional structure of a protein is determined by its amino acid sequence. Here we show that a substantial population of proteins from the NusG superfamily of transcription factors do not adhere to this paradigm. Previous work demonstrated that one member of this superfamily has a regulatory domain that completely switches between α-helical and β-sheet folds, but the pervasiveness of this fold-switching mechanism is uncertain. To address this question, we developed a sequence-based predictor, which revealed that thousands of proteins from this superfamily switch folds. Circular dichroism and nuclear magnetic resonance spectroscopies of 10 sequence-diverse variants confirmed our predictions. By contrast, state-of-the-art methods based on the protein folding paradigm assume that related sequences adopt the same fold and thus predicted that the regulatory domains of all variants adopt only the β-sheet fold. Removal of this bias revealed that residue-residue contacts from both α-helical and β-sheet folds are conserved in a large subpopulation of fold-switching domains, poising them to assume disparate conformations. Our results suggest that fold switching is a pervasive mechanism of transcriptional regulation in all kingdoms of life and indicate that expanding the protein folding paradigm may reveal the involvement of fold-switching proteins in diverse biological processes.</p>
},
	issn = {00063495},
	doi = {10.1016/j.bpj.2021.11.1945},
	url = {https://linkinghub.elsevier.com/retrieve/pii/S0006349521029209},
	author = {Porter, Lauren L. and Kim, Allen and Looger, Loren and Majumdar, Ananya K. and Starich, Mary}
}
