Inaccurate secondary structure predictions often indicate protein fold switching

Mishra, Soumya Ranjan; Looger, Loren L.; Porter, Lauren L.

doi:10.1002/pro.3664

Cited by 32 publications

(52 citation statements)

References 41 publications

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“…These results are consistent with previous work showing that secondary structure predictions tend to predict coil least accurately. These results are also largely consistent with our previous work (2), which showed that coil <-> helix or coil <-> strand discrepancies were more common for non-fold-switching (i.e. single-fold) regions of proteins.…”

Section: Discussionsupporting

confidence: 93%

“…These pathways support the hypothesis that proteins with novel folds and functions can evolve through stepwise mutation (10,11). Secondly, because evolved fold switchers challenge the notion that similar amino sequences reliably encode the same protein fold, they could potentially be used to improve methods for protein structure prediction (2) and protein design (12).…”

Section: Introductionmentioning

confidence: 63%

“…To do this, we quantified the number of a<->b discrepancies between evolved fold switchers and normalized them by the minimum number of secondary structure annotations from one of the two folds. Table 3 shows that JPred4 yields significantly higher a<->b discrepancies than the previously published value of 6% for single-fold proteins (2). The other two predictors gave much lower frequencies of a<->b discrepancies, mostly within error of 0%, with the notable exception of SPIDER3's Cro:cI value of 15±4.8%.…”

Section: Secondary Structure Prediction Discrepancies Can Identify Evmentioning

confidence: 71%

“…Previous work suggests that these discrepancies can be enriched in fold switchers compared to singlefold proteins (2). To do this, we quantified the number of a<->b discrepancies between evolved fold switchers and normalized them by the minimum number of secondary structure annotations from one of the two folds.…”

Section: Secondary Structure Prediction Discrepancies Can Identify Evmentioning

confidence: 99%

“…Previously we showed that secondary structure predictions inconsistent with experimentally determined secondary structures can be used to identify extant fold-switching proteins (2). These proteins, in contrast to evolved fold switchers, have a single amino acid sequence that adopts different folds and functions in response to cellular stimuli (1).…”

Section: Introductionmentioning

confidence: 99%

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A method for predicting evolved fold switchers exclusively from their sequences

Kim

Looger

Porter

2020

Preprint

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Although most proteins with known structures conform to the longstanding rule-of-thumb that high levels of aligned sequence identity tend to indicate similar folds and functions, an increasing number of exceptions is emerging. In spite of having highly similar sequences, these "evolved fold switchers" (1) can adopt radically different folds with disparate biological functions. Predictive methods for identifying evolved fold switchers are desirable because some of them are associated with disease and/or can perform different functions in cells. Previously, we showed that inconsistencies between predicted and experimentally determined secondary structures can be used to predict fold switching proteins (2). The usefulness of this approach is limited, however, because it requires experimentally determined protein structures, whose magnitude is dwarfed by the number of genomic proteins. Here, we use secondary structure predictions to identify evolved fold switchers from their amino acid sequences alone. To do this, we looked for inconsistencies between the secondary structure predictions of the alternative conformations of evolved fold switchers. We used three different predictors in this study: JPred4, PSIPRED, and SPIDER3. We find that overall inconsistencies are not a significant predictor of evolved fold switchers for any of the three predictors.Inconsistencies between a-helix and b-strand predictions made by JPred4, however, can discriminate between the different conformations of evolved fold switchers with statistical significance (p < 1.7*10 -13 ). In light of this observation, we used these inconsistencies as a classifier and found that it could robustly discriminate between evolved fold switchers and evolved non-fold-switchers, as evidenced by a Matthews correlation coefficient of 0.90. These results indicate that inconsistencies between secondary structure predictions can indeed be used to identify evolved fold switchers from their genomic sequences alone. Our findings have implications for genomics, structural biology, and human health.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 63%

Section: Secondary Structure Prediction Discrepancies Can Identify Evmentioning

confidence: 71%

Section: Secondary Structure Prediction Discrepancies Can Identify Evmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A method for predicting evolved fold switchers exclusively from their sequences

Kim

Looger

Porter

2020

Preprint

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Fluid protein fold space and its implications

Porter

2023

BioEssays

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Fold‐switching proteins, which remodel their secondary and tertiary structures in response to cellular stimuli, suggest a new view of protein fold space. For decades, experimental evidence has indicated that protein fold space is discrete: dissimilar folds are encoded by dissimilar amino acid sequences. Challenging this assumption, fold‐switching proteins interconnect discrete groups of dissimilar protein folds, making protein fold space fluid. Three recent observations support the concept of fluid fold space: (1) some amino acid sequences interconvert between folds with distinct secondary structures, (2) some naturally occurring sequences have switched folds by stepwise mutation, and (3) fold switching is evolutionarily selected and likely confers advantage. These observations indicate that minor amino acid sequence modifications can transform protein structure and function. Consequently, proteomic structural and functional diversity may be expanded by alternative splicing, small nucleotide polymorphisms, post‐translational modifications, and modified translation rates.

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A high‐throughput predictive method for sequence‐similar fold switchers

2021

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Although most experimentally characterized proteins with similar sequences assume the same folds and perform similar functions, an increasing number of exceptions is emerging. One class of exceptions comprises sequence-similar fold switchers, whose secondary structures shift from α-helix <-> β-sheet through a small number of mutations, a sequence insertion, or a deletion. Predictive methods for identifying sequence-similar fold switchers are desirable because some are associated with disease and/or can perform different functions in cells. Here, we use homology-based secondary structure predictions to identify sequence-similar fold switchers from their amino acid sequences alone. To do this, we predicted the secondary structures of sequence-similar fold switchers using three different homology-based secondary structure predictors: PSIPRED, JPred4, and SPIDER3. We found that α-helix <-> β-strand prediction discrepancies from JPred4 discriminated between the different conformations of sequencesimilar fold switchers with high statistical significance (P < 1.8*10 −19 ). Thus, we used these discrepancies as a classifier and found that they can often robustly discriminate between sequence-similar fold switchers and sequence-similar proteins that maintain the same folds (Matthews Correlation Coefficient of 0.82). We found that JPred4 is a more robust predictor of sequence-similar fold switchers because of (a) the curated sequence database it uses to produce multiple sequence alignments and (b) its use of sequence profiles based on Hidden Markov Models. Our results indicate that inconsistencies between JPred4 secondary structure predictions can be used to identify some sequence-similar fold switchers from their sequences alone. Thus, the negative information from inconsistent secondary structure predictions can potentially be leveraged to identify sequence-similar fold switchers from the broad base of genomic sequences.

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Inaccurate secondary structure predictions often indicate protein fold switching

Cited by 32 publications

References 41 publications

A method for predicting evolved fold switchers exclusively from their sequences

A method for predicting evolved fold switchers exclusively from their sequences

Fluid protein fold space and its implications

A high‐throughput predictive method for sequence‐similar fold switchers

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