The Amazing World of IDPs in Human Diseases

Monti, Simona Maria; Simone, Giuseppina De; Langella, Emma

doi:10.3390/biom11020333

Cited by 7 publications

(4 citation statements)

References 15 publications

(17 reference statements)

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“…The presence of structural flexibility allows them to attain different conformations in different environmental conditions. The interactions of disordered proteins involved in transcriptional regulation have critically enhanced the information about the expression profiling of the eukaryotic cells ( Uversky, 2018 ; Monti et al., 2021 ; Uversky et al., 2008 ). In general, structural transitions in IDPs are challenging to identify and poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Transactivation domain of Adenovirus Early Region 1A (E1A): Investigating folding dynamics and aggregation

Sharma¹,

Gadhave²,

Kumar³

et al. 2022

Current Research in Structural Biology

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Transactivation domain of Adenovirus Early region 1A (E1A) oncoprotein is an intrinsically disordered molecular hub protein. It is involved in binding to different domains of human cell transcriptional co-activators such as retinoblastoma (pRb), CREB-binding protein (CBP), and its paralogue p300. The conserved region 1 (TAD) of E1A is known to undergo structural transitions and folds upon interaction with transcriptional adaptor zinc finger 2 (TAZ2). Previous reports on Taz2-E1A studies have suggested the formation of helical conformations of E1A-TAD. However, the folding behavior of the TAD region in isolation has not been studied in detail. Here, we have elucidated the folding behavior of E1A peptide at varied temperatures and solution conditions. Further, we have studied the effects of macromolecular crowding on E1A-TAD peptide. Additionally, we have also predicted the molecular recognition features of E1A using MoRF predictors. The predicted MoRFs are consistent with its structural transitions observed during TAZ2 interactions for transcriptional regulation in literature. Also, as a general rule of MoRFs, E1A undergoes helical transitions in alcohol and osmolyte solution. Finally, we studied the aggregation behavior of E1A, where we observed that the E1A could form amyloid-like aggregates that are cytotoxic to mammalian cells.

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Section: Discussionmentioning

confidence: 99%

Transactivation domain of Adenovirus Early Region 1A (E1A): Investigating folding dynamics and aggregation

Sharma¹,

Gadhave²,

Kumar³

et al. 2022

Current Research in Structural Biology

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“…The same trend holds for an ever-increasing emergence of disease-associated genes in more recent speciation events ( Dickerson & Robertson, 2012 ; Lopez-Bigas & Ouzounis, 2004 ), raising the question whether specific residues can be directly implicated in particular diseases. A correlation between intrinsic disorder and various human diseases such as cancer, diabetes, amyloidosis, and neurodegenerative diseases has already been established in specific cases ( Choudhary et al , 2022 ; Monti et al , 2021 , 2022 ), and is emerging as a significant biomedical research endeavour.…”

Section: Introductionmentioning

confidence: 99%

Disease association and comparative genomics of compositional bias in human proteins

et al. 2023

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Background: The evolutionary rate of disordered protein regions varies greatly due to the lack of structural constraints. So far, few studies have investigated the presence/absence patterns of compositional bias, indicative of disorder, across phylogenies in conjunction with human disease. In this study, we report a genome-wide analysis of compositional bias association with disease in human proteins and their taxonomic distribution. Methods: The human genome protein set provided by the Ensembl database was annotated and analysed with respect to both disease associations and the detection of compositional bias. The Uniprot Reference Proteome dataset, containing 11297 proteomes was used as target dataset for the comparative genomics of a well-defined subset of the Human Genome, including 100 characteristic, compositionally biased proteins, some linked to disease. Results: Cross-evaluation of compositional bias and disease-association in the human genome reveals a significant bias towards biased regions in disease-associated genes, with charged, hydrophilic amino acids appearing as over-represented. The phylogenetic profiling of 17 disease-associated, proteins with compositional bias across 11297 proteomes captures characteristic taxonomic distribution patterns. Conclusions: This is the first time that a combined genome-wide analysis of compositional bias, disease-association and taxonomic distribution of human proteins is reported, covering structural, functional, and evolutionary properties. The reported framework can form the basis for large-scale, follow-up projects, encompassing the entire human genome and all known gene-disease associations.

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“…Intrinsically disordered proteins (IDPs) are a widespread class of proteins with the ability to quickly change their conformations upon participating in biological processes [ 1 ]. IDP structures are highly controlled in the cell, and aberrant regulation is often associated with protein aggregation and human diseases [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Trehalose and Ceftriaxone on the Stability of Aggregating-Prone Tau Peptide Containing PHF6* Sequence: An SRCD Study

Honisch

Torni

Hussain

et al. 2022

IJMS

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The tau protein, a soluble protein associated with microtubules, which is involved in the assembly and stabilization of cytoskeletal elements, was found to form neurofibrillary tangles in different neurodegenerative diseases. Insoluble tau aggregates were observed to be organized in paired helical filaments (PHFs) and straight filaments (SFs). Recently, two small sequences (306–311 and 275–280) in the microtubule-binding region (MTBR), named PHF6 and PHF6*, respectively, were found to be essential for tau aggregation. Since a possible therapeutic approach consists of impairing amyloid formation either by stabilizing the native proteins or reducing the level of amyloid precursors, here we use synchrotron radiation circular dichroism (SRCD) at Diamond B23 beamline to evaluate the inhibitory effects of two small molecules, trehalose and ceftriaxone, against the aggregation of a small peptide containing the PHF6* sequence. Our results indicate that both these molecules, ceftriaxone and trehalose, increased the stability of the peptide toward aggregation, in particular that induced by heparin. With trehalose being present in many fruits, vegetables, algae and processed foods, these results support the need to investigate whether a diet richer in trehalose might exert a protective effect toward pathologies linked to protein misfolding.

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The Amazing World of IDPs in Human Diseases

Abstract: It has been clearly established that some proteins or protein regions are devoid of any stable secondary and/or tertiary structure under physiological conditions, but still possess fundamental biological functions [...]

Cited by 7 publications

References 15 publications

Transactivation domain of Adenovirus Early Region 1A (E1A): Investigating folding dynamics and aggregation

Transactivation domain of Adenovirus Early Region 1A (E1A): Investigating folding dynamics and aggregation

Disease association and comparative genomics of compositional bias in human proteins

Effect of Trehalose and Ceftriaxone on the Stability of Aggregating-Prone Tau Peptide Containing PHF6* Sequence: An SRCD Study

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