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Anatomy of protein disorder, flexibility and disease-related mutations.

ABSTRACT: Integration of protein structural information with human genetic variation and pathogenic mutations is essential to understand molecular mechanisms associated with the effects of polymorphisms on protein interactions and cellular processes. We investigate occurrences of non-synonymous SNPs in ordered and disordered protein regions by systematic mapping of common variants and disease-related SNPs onto these regions. We show that common variants accumulate in disordered regions; conversely pathogenic variants are significantly depleted in disordered regions. These different occurrences of pathogenic and common SNPs can be attributed to a negative selection on random mutations in structurally highly constrained regions. New approaches in the study of quantitative effects of pathogenic-related mutations should effectively account for all the possible contexts and relative functional constraints in which the sequence variation occurs.

SUBMITTER: Lu HC

PROVIDER: S-EPMC4532925 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Anatomy of protein disorder, flexibility and disease-related mutations.

Lu Hui-Chun HC Chung Sun Sook SS Fornili Arianna A Fraternali Franca F

Frontiers in molecular biosciences 20150812

Integration of protein structural information with human genetic variation and pathogenic mutations is essential to understand molecular mechanisms associated with the effects of polymorphisms on protein interactions and cellular processes. We investigate occurrences of non-synonymous SNPs in ordered and disordered protein regions by systematic mapping of common variants and disease-related SNPs onto these regions. We show that common variants accumulate in disordered regions; conversely pathoge ...[more]

PMID: 26322316

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Project description:The effects of disease mutations on protein structure and function have been extensively investigated, and many predictors of the functional impact of single amino acid substitutions are publicly available. The majority of these predictors are based on protein structure and evolutionary conservation, following the assumption that disease mutations predominantly affect folded and conserved protein regions. However, the prevalence of the intrinsically disordered proteins (IDPs) and regions (IDRs) in the human proteome together with their lack of fixed structure and low sequence conservation raise a question about the impact of disease mutations in IDRs. Here, we investigate annotated missense disease mutations and show that 21.7% of them are located within such intrinsically disordered regions. We further demonstrate that 20% of disease mutations in IDRs cause local disorder-to-order transitions, which represents a 1.7-2.7 fold increase compared to annotated polymorphisms and neutral evolutionary substitutions, respectively. Secondary structure predictions show elevated rates of transition from helices and strands into loops and vice versa in the disease mutations dataset. Disease disorder-to-order mutations also influence predicted molecular recognition features (MoRFs) more often than the control mutations. The repertoire of disorder-to-order transition mutations is limited, with five most frequent mutations (R?W, R?C, E?K, R?H, R?Q) collectively accounting for 44% of all deleterious disorder-to-order transitions. As a proof of concept, we performed accelerated molecular dynamics simulations on a deleterious disorder-to-order transition mutation of tumor protein p63 and, in agreement with our predictions, observed an increased ?-helical propensity of the region harboring the mutation. Our findings highlight the importance of mutations in IDRs and refine the traditional structure-centric view of disease mutations. The results of this study offer a new perspective on the role of mutations in disease, with implications for improving predictors of the functional impact of missense mutations.

Project description:Findings from studies investigating cognitive flexibility in eating disorders (EDs) are inconsistent, and although neuropsychological tests are commonly used to measure these skills, they may not be particularly effective in predicting everyday functioning. Also, extant studies have largely focused on flexibility in anorexia nervosa (AN), with assessments targeting general rather than specific flexibility, and cognitive, rather than behavioral flexibility. Knowledge regarding ED specific flexibility and flexibility in bulimia nervosa (BN) and binge eating disorder (BED) is still scarce. The aim of this study was to develop and validate a novel measure assessing general and ED specific flexibility in a diagnostically diverse sample, and in healthy controls (HCs). A sample of 207 adult individuals with EDs (55% AN, 29% BN, 16% BED) and 288 HCs responded to an online, 51-item, pilot questionnaire on ED specific and general flexibility. In addition, participants completed the shift subscale from the Behavior Rating Inventory of Executive Function Adult version (BRIEF-A), and the Eating Disorder Diagnostic Scale (EDDS). A principal component analysis (PCA) in the clinical sample yielded a 36-item, three-factor solution capturing general flexibility, flexibility related to food and exercise, and flexibility concerning body shape and weight. Results showed that the measure had good to excellent internal consistency, and good convergent validity. A confirmatory factor analysis (CFA) using data from HCs revealed good fit indexes, supporting the original factor solution. A receiver operating characteristics analysis (ROC) demonstrated excellent accuracy in distinguishing scores from those with and without EDs. A cutoff score of 136 yielded the most balanced sensitivity and specificity. Significant differences in general and ED specific flexibility were found between individuals with and without EDs. Overall, HCs achieved the highest flexibility scores, followed by those with BED, BN, and AN. In sum this novel measure, the Eating Disorder Flexibility Index (EDFLIX) questionnaire, was found to be reliable and valid in the assessment of cognitive and behavioral flexibility, with results offering support for the conceptual distinction between general and ED related flexibility. The study also provides strong evidence for the discriminant validity of the EDFLIX with results revealing significant differences in flexibility in people with and without EDs. In addition, significant differences in flexibility also emerged when comparing diagnostic groups, indicating the utility of the assessment instrument for classification purposes.

Dataset Information

Anatomy of protein disorder, flexibility and disease-related mutations.

Publications

Anatomy of protein disorder, flexibility and disease-related mutations.

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