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Self-aggregation and coaggregation of the p53 core fragment with its aggregation gatekeeper variant.

ABSTRACT: Recent studies suggested that p53 aggregation can lead to loss-of-function (LoF), dominant-negative (DN) and gain-of-function (GoF) effects, with adverse cancer consequences. The p53 aggregation-nucleating (251)ILTIITL(257) fragment is a key segment in wild-type p53 aggregation; however, an I254R mutation can prevent it. It was suggested that self-assembly of wild-type p53 and its cross-interaction with mutants differ from the classical amyloid nucleation-growth mechanism. Here, using replica exchange molecular dynamics (REMD) simulations, we studied the cross-interactions of this p53 core fragment and its aggregation rescue I254R mutant. We found that the core fragment displays strong aggregation propensity, whereas the gatekeeper I254R mutant tends to be disordered, consistent with experiments. Our cross-interaction results reveal that the wild-type p53 fragment promotes ?-sheet formation of the I254R mutant by shifting the disordered mutant peptides into aggregating states. As a result, the system has similar oligomeric structures, inter-peptide interactions and free energy landscape as the wild type fragment does, revealing a prion-like process. We also found that in the cross-interaction system, the wild-type species has higher tendency to interact with the mutant than with itself. This phenomenon illustrates synergistic effects between the p53 (251)ILTIITL(257) fragment and the mutant resembling prion cross-species propagation, cautioning against exploiting it in drug discovery.

SUBMITTER: Lei J

PROVIDER: S-EPMC6456058 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Self-aggregation and coaggregation of the p53 core fragment with its aggregation gatekeeper variant.

Lei Jiangtao J Qi Ruxi R Wei Guanghong G Nussinov Ruth R Ma Buyong B

Physical chemistry chemical physics : PCCP 20160301 11

Recent studies suggested that p53 aggregation can lead to loss-of-function (LoF), dominant-negative (DN) and gain-of-function (GoF) effects, with adverse cancer consequences. The p53 aggregation-nucleating (251)ILTIITL(257) fragment is a key segment in wild-type p53 aggregation; however, an I254R mutation can prevent it. It was suggested that self-assembly of wild-type p53 and its cross-interaction with mutants differ from the classical amyloid nucleation-growth mechanism. Here, using replica ex ...[more]

PMID: 26923710

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Project description:ImportanceClarification of the joint influence of familial patterns of suicide attempts and comorbid mental disorders can enhance the understanding and prevention of suicide attempts.ObjectiveTo investigate the familial patterns of suicide attempts and comorbid mental disorders and their associations in a 2-site family study of mood and anxiety disorders.Design, setting, and participantsData were obtained from 2 parallel community-based family studies conducted in the United States (National Institute of Mental Health [NIMH] study) and in Lausanne, Switzerland (PsyCoLaus study), on the comorbidity of mood and anxiety disorders. The study sample comprised 1119 adult probands and 5355 first-degree relatives. Data were collected and analyzed from October 2004 to December 2016.Main outcomes and measuresLifetime suicide attempt and mental disorders in first-degree relatives, obtained through direct interviews or family history reports.ResultsThe study included 1119 adult probands (675 female [60.3%] and a mean [SD] age of 50 [12.0] years) and 5355 first-degree relatives (2752 female [51.4%] and a mean [SD] age of 52 [1.5] years). Of these participants, 90 (8.0%) of 1119 probands and 199 (3.7%) of 5355 relatives had a lifetime history of suicide attempt. Those with such a history had higher rates of all mental disorders, a greater number of disorders, and statistically significantly poorer current and lifetime global functioning. After adjustment for age and sex, a statistically significant association between suicide attempts in probands and in relatives was found at the NIMH site (OR, 2.6; 95% CI, 1.5-4.7), at the Lausanne site (OR, 3.1; 95% CI, 1.6-6.0), and in the combined data (OR, 2.9; 95% CI, 1.9-4.5). All mood disorder subtypes and substance use disorders were statistically significantly associated with suicide attempts. The familial association between lifetime suicide attempts in probands and relatives was not statistically significant for the combined sample (OR, 1.6; 95% CI, 1.0-2.7) after adjustment for comorbid conditions in probands and relatives. Social anxiety disorder in probands was associated with suicide attempts in relatives (OR, 2.4; 95% CI, 1.7-3.5) after controlling for comorbid mood, anxiety, and substance use disorders.Conclusions and relevanceFamiliality of suicide attempts appears to be explained by a history of mental disorders among those with suicide attempts; the novel finding of a common familial diathesis for suicide attempts and social anxiety, particularly in combination with mood disorders, has heuristic value for future research and may be a risk marker that can inform prevention efforts.

Dataset Information

Self-aggregation and coaggregation of the p53 core fragment with its aggregation gatekeeper variant.

Publications

Self-aggregation and coaggregation of the p53 core fragment with its aggregation gatekeeper variant.

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