The Amazing World of IDPs in Human Diseases II

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

doi:10.3390/biom12030369

Cited by 4 publications

(2 citation statements)

References 15 publications

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“…Because of their importance in cellular interaction, IDPs are tightly regulated and, when altered, are implicated in various diseases [ 9 ]. More specifically, IDPs have been analyzed in the context of cancer, cardiovascular, and neurodegenerative disease and are postulated as a target for therapeutic modalities [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Lee

Procopio

Pulido

et al. 2023

IJMS

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Intrinsically disordered regions (IDRs) are protein regions that are unable to fold into stable tertiary structures, enabling their involvement in key signaling and regulatory functions via dynamic interactions with diverse binding partners. An understanding of IDRs and their association with biological function may help elucidate the pathogenesis of inherited retinal diseases (IRDs). The main focus of this work was to investigate the degree of disorder in 14 proteins implicated in IRDs and their relationship with the number of pathogenic missense variants. Metapredict, an accurate, high-performance predictor that reproduces consensus disorder scores, was used to probe the degree of disorder as a function of the amino acid sequence. Publicly available data on gnomAD and ClinVar was used to analyze the number of pathogenic missense variants. We show that proteins with an over-representation of missense variation exhibit a high degree of disorder, and proteins with a high amount of disorder tolerate a higher degree of missense variation. These proteins also exhibit a lower amount of pathogenic missense variants with respect to total missense variants. These data suggest that protein function may be related to the overall level of disorder and could be used to refine variant interpretation in IRDs.

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Section: Introductionmentioning

confidence: 99%

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Lee

Procopio

Pulido

et al. 2023

IJMS

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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.

show abstract

Disease association and comparative genomics of compositional bias in human proteins

et al. 2023

View full text Add to dashboard Cite

Background: The evolutionary rate of disordered proteins varies greatly due to the lack of structural constraints. So far, few studies have investigated the presence/absence patterns of intrinsically disordered regions (IDRs) 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 low complexity regions in disease-associated genes, with charged, hydrophilic amino acids appearing as over-represented. The phylogenetic profiling of 17 disease-associated, low complexity proteins across 11297 proteomes captures characteristic taxonomic distribution patterns. Conclusions: This is the first time that a combined genome-wide analysis of low complexity, 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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The Amazing World of IDPs in Human Diseases II

Abstract: Intrinsically Disordered Proteins (IDPs) lack stable tertiary and secondary structures and are extensively distributed across eukaryotic cells, playing critical roles in cell signaling and regulation. [...]

Cited by 4 publications

References 15 publications

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Disease association and comparative genomics of compositional bias in human proteins

Disease association and comparative genomics of compositional bias in human proteins

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