AlphaFold2 has revolutionized protein structure prediction by leveraging sequence information to rapidly model protein folds with atomic‐level accuracy. Nevertheless, previous work has shown that ...these predictions tend to be inaccurate for structurally heterogeneous proteins. To systematically assess factors that contribute to this inaccuracy, we tested AlphaFold2's performance on 98‐fold‐switching proteins, which assume at least two distinct‐yet‐stable secondary and tertiary structures. Topological similarities were quantified between five predicted and two experimentally determined structures of each fold‐switching protein. Overall, 94% of AlphaFold2 predictions captured one experimentally determined conformation but not the other. Despite these biased results, AlphaFold2's estimated confidences were moderate‐to‐high for 74% of fold‐switching residues, a result that contrasts with overall low confidences for intrinsically disordered proteins, which are also structurally heterogeneous. To investigate factors contributing to this disparity, we quantified sequence variation within the multiple sequence alignments used to generate AlphaFold2's predictions of fold‐switching and intrinsically disordered proteins. Unlike intrinsically disordered regions, whose sequence alignments show low conservation, fold‐switching regions had conservation rates statistically similar to canonical single‐fold proteins. Furthermore, intrinsically disordered regions had systematically lower prediction confidences than either fold‐switching or single‐fold proteins, regardless of sequence conservation. AlphaFold2's high prediction confidences for fold switchers indicate that it uses sophisticated pattern recognition to search for one most probable conformer rather than protein biophysics to model a protein's structural ensemble. Thus, it is not surprising that its predictions often fail for proteins whose properties are not fully apparent from solved protein structures. Our results emphasize the need to look at protein structure as an ensemble and suggest that systematic examination of fold‐switching sequences may reveal propensities for multiple stable secondary and tertiary structures.
Extant fold-switching proteins are widespread Porter, Lauren L.; Looger, Loren L.
Proceedings of the National Academy of Sciences - PNAS,
06/2018, Letnik:
115, Številka:
23
Journal Article
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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.
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.
Fold switching suggests that protein fold space is more fluid than previously realized because homologous amino acid sequences can assume multiple folds with different secondary structure arrangements. In this figure, fold switching allows groups of homologous sequences (colored contours) to span different regions of protein fold space.
Extant fold‐switching proteins remodel their secondary structures and change their functions in response to environmental stimuli. These shapeshifting proteins regulate biological processes and are ...associated with a number of diseases, including tuberculosis, cancer, Alzheimer's, and autoimmune disorders. Thus, predictive methods are needed to identify more fold‐switching proteins, especially since all naturally occurring instances have been discovered by chance. In response to this need, two high‐throughput predictive methods have recently been developed. Here we test them on ORF9b, a newly discovered fold switcher and potential therapeutic target from the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2). Promisingly, both methods correctly indicate that ORF9b switches folds. We then tested the same two methods on ORF9b1, the ORF9b homolog from SARS‐CoV‐1. Again, both methods predict that ORF9b1 switches folds, a finding consistent with experimental binding studies. Together, these results (a) demonstrate that protein fold switching can be predicted using high‐throughput computational approaches and (b) suggest that fold switching might be a general characteristic of ORF9b homologs.
Since 1990, the world's homicide rate has declined by nearly 20%. While prior research has documented parallel homicide declines across many individual countries, the causes of a shared international ...homicide decline remain unknown. Drawing on a worldwide process of population ageing, and on research linking age to criminal activity, this study investigates the contribution of global demographic shifts to the international homicide decline.
We draw from (1) a High Coverage Sample of 126 countries since 1990, and (2) a Long Series Sample of 26 countries since 1960 and utilize fixed-effect regressions to evaluate the impact of age structure on homicide trends. In addition, we use a quantile regression to explore variations in the relationship between age structure and homicide conditional on homicide levels.
Results using the High Coverage Sample suggest no relationship between age structure and homicide. However, results from the Long Series Sample suggest that changes in the relative size of countries' youth population is a major predictor of homicide trends since 1960. In exploring this divergence, we find that the influence of age structure on homicide becomes less evident as other risk factors for violence gain prominence. Thus, while high homicide countries had the most to gain from falling homicide rates, the safety benefits of an ageing population have been concentrated among the least violent countries.
While the homicide declines of individual countries have often been attributed to domestic policies, the universality of international homicide trends suggests the influence of broader global phenomenon. We find that countries' homicide trends are strongly associated with changes in the size of their youth populations, particularly where there are few competing criminogenic forces. Based on these results, we propose an explanation for the international homicide decline, while highlighting the importance of demographic patterns in explaining homicide trends.
This study investigates the link between incarceration and health behavior among a sample of young adults from the National Longitudinal Study of Adolescent Health (N = 1,670). The association is ...analyzed using propensity score methods and a strategic comparison group: respondents who have been convicted of crimes, but not incarcerated. Findings suggest that former inmates consume more fast food and have a higher likelihood of smoking than do similarly situated peers. These associations operate partly through increased financial strife and decreased social standing. Given the role of health behavior in predicting future health outcomes, poor health behavior may be a salient force driving health and mortality risk among the formerly incarcerated population.
This study examines the association between prior incarceration and health insurance status and whether living in a state adopting the Affordable Care Act (ACA) Medicaid expansion moderates this ...relationship.
Data are from the National Longitudinal Study of Adolescent to Adult Health (Wave I 1993-1994, Wave IV 2008, and Wave V 2016-2018; N=8,965). Multiple logistic regression with multiplicative interaction terms were performed to assess the relationship between previous incarceration and ACA Medicaid expansion on (1) being insured and (2) being on public health insurance. Analyses were performed in 2023.
Findings demonstrate a positive and statistically significant interaction in the association between previous incarceration and living in a state with ACA Medicaid expansion on having public health insurance (OR=2.402; 95% CI=1.257, 4.588).
The ACA Medicaid expansion was associated with a greater likelihood of public health insurance coverage for formerly incarcerated persons in the U.S. These findings suggest that Medicaid expansion could be critical in improving health insurance coverage among formerly incarcerated individuals who are a population that is more likely to be uninsured.
Abstract
Although most globular proteins fold into a single stable structure, an increasing number have been shown to remodel their secondary and tertiary structures in response to cellular stimuli. ...State-of-the-art algorithms predict that these fold-switching proteins adopt only one stable structure, missing their functionally critical alternative folds. Why these algorithms predict a single fold is unclear, but all of them infer protein structure from coevolved amino acid pairs. Here, we hypothesize that coevolutionary signatures are being missed. Suspecting that single-fold variants could be masking these signatures, we developed an approach, called Alternative Contact Enhancement (ACE), to search both highly diverse protein superfamilies–composed of single-fold and fold-switching variants–and protein subfamilies with more fold-switching variants. ACE successfully revealed coevolution of amino acid pairs uniquely corresponding to both conformations of 56/56 fold-switching proteins from distinct families. Then, we used ACE-derived contacts to (1) predict two experimentally consistent conformations of a candidate protein with unsolved structure and (2) develop a blind prediction pipeline for fold-switching proteins. The discovery of widespread dual-fold coevolution indicates that fold-switching sequences have been preserved by natural selection, implying that their functionalities provide evolutionary advantage and paving the way for predictions of diverse protein structures from single sequences.
The findings from a growing body of research reveal that incarceration is detrimental for both physical and mental health. Incarceration, however, is typically conceptualized and operationalized as a ...dichotomy; individuals either have, or have not, been incarcerated. Considering that incarceration can range from one day to several years, a dichotomous measure may be overlooking important variations across lengths of exposure. In addition, most inmates are incarcerated more than once. In this study, we help to fill this gap by examining the relationship between incarceration dosage, measured as time served and number of spells, and mental health among a sample of young adults from the National Longitudinal Study of Youth 1997. By using fixed‐effects modeling, we find that the number of spells and the months incarcerated are positively related to mental health symptoms and the likelihood of depression. The association, however, is contingent on whether a respondent is currently or formerly incarcerated. Among current inmates, more time served is expected to improve mental health and the number of spells is unrelated to either outcome.
Fold-switching proteins respond to cellular stimuli by remodeling their secondary structures and changing their functions. Whereas several previous reviews have focused on various structural, ...physical-chemical, and evolutionary aspects of this newly emerging class of proteins, this minireview focuses on how fold switching modulates protein function and regulates biological processes. It first compares and contrasts fold switchers with other known types of proteins. Second, it presents examples of how various proteins can change their functions through fold switching. Third, it demonstrates that fold switchers can regulate biological processes by discussing two proteins, RfaH and KaiB, whose dramatic secondary structure remodeling events directly affect gene expression and a circadian clock, respectively. Finally, this minireview discusses how the field of protein fold switching might advance.
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•Fold-switching proteins remodel their secondary structures in response to stimuli•Six observed varieties of remodeling foster diverse functional changes•Fold-switching proteins regulate gene expression and a circadian clock's periodicity•Several approaches hold promise for the discovery of more fold switchers
Fold-switching proteins remodel their secondary structures and change their functions in response to cellular stimuli. Kim and Porter discuss how the dramatic conformational changes in these proteins help to regulate biological processes, such as bacterial gene expression and the periodicity of the cyanobacterial circadian clock.
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