Extant fold-switching proteins are widespread

By Lauren L. Porter, L. Looger. 2018

187 citations recorded by the source corpus.

Significance It is commonly thought that each globular protein has a single 3D structure, or fold, that fosters its function. In contrast, recent studies have identified several fold-switching proteins whose secondary structures can be remodeled in response to cellular stimuli. Although thought to be rare, we found 96 literature-validated fold-switching proteins by exhaustively searching the database of protein structures [Protein Data Bank (PDB)]. Characterizing these proteins led us to hypothesize that their abundance may be underrepresented in the PDB. Thus, we developed a computational method that identifies fold-switching proteins and used it to estimate that 0.5–4% of PDB proteins switch folds. These results suggest that proteins switch folds with significant frequency, which has implications for cell biology, genomics, and human health. A central tenet of biology is that globular proteins have a unique 3D structure under physiological conditions. Recent work has challenged this notion by demonstrating that some proteins switch folds, a process that involves remodeling of secondary structure in response to a few mutations (evolved fold switchers) or cellular stimuli (extant fold switchers). To date, extant fold switchers have been viewed as rare byproducts of evolution, but their frequency has been neither quantified nor estimated. By systematically and exhaustively searching the Protein Data Bank (PDB), we found ∼100 extant fold-switching proteins. Furthermore, we gathered multiple lines of evidence suggesting that these proteins are widespread in nature. Based on these lines of evidence, we hypothesized that the frequency of extant fold-switching proteins may be underrepresented by the structures in the PDB. Thus, we sought to identify other putative extant fold switchers with only one solved conformation. To do this, we identified two characteristic features of our ∼100 extant fold-switching proteins, incorrect secondary structure predictions and likely independent folding cooperativity, and searched the PDB for other proteins with similar features. Reassuringly, this method identified dozens of other proteins in the literature with indication of a structural change but only one solved conformation in the PDB. Thus, we used it to estimate that 0.5–4% of PDB proteins switch folds. These results demonstrate that extant fold-switching proteins are likely more common than the PDB reflects, which has implications for cell biology, genomics, and human health.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

Prediction of multiple conformational states by combining sequence clustering with AlphaFold2 (2022, methodology): “If Porter and Looger’s estimate 17 that 0.5-4% of all proteins contain fold-switching domains is accurate, this would correspond to roughly 1-8 million fold-switching proteins present.”
AlphaFold2 fails to predict protein fold switching (2022, methodology): “AlphaFold2 was trained on the PDB, which contains mostly single-fold proteins.(9)”
Coevolution‐derived native and non‐native contacts determine the emergence of a novel fold in a universally conserved family of transcription factors (2022, background): “5% and 4% of proteins whose structures are deposited in the PDB are likely to exhibit fold-switching, or metamorphic, behavior.(8) Among them, RfaH is one of the most studied cases due”
Many dissimilar NusG protein domains switch between α-helix and β-sheet folds (2022, background): “(2) Some annotated NusGs have RfaH-like CD spectra (variant #4), likely the result of incorrect annotation.”