ActiveDriverDB: human disease mutations and genome variation in post-translational modification sites of proteins

Krassowski, Michal; Paczkowska, Marta; Cullion, Kim; Huang, Tina; Dzneladze, Irakli; Ouellette, B. F. Francis; Yamada, Joseph Tadashi; Fradet-Turcotte, Amélie; Reimand, Jüri

doi:10.1093/nar/gkx973

Cited by 85 publications

(77 citation statements)

References 70 publications

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“…Given the strong connection between PTMs, metabolism, and protein functions, several groups found that disease causing mutations or single nucleotide polymorphisms (SNPs) in patients can coincide with PTM sites (see ActiveDriver and AWESOME databases). Similarly, SNPs at PTM sites of proteins in long‐lived mammals may generate proteoforms that promote healthy aging.…”

Section: Longevity‐specific Ptm Sites?mentioning

confidence: 99%

Proteomics of Long‐Lived Mammals

et al. 2020

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Mammalian species differ up to 100‐fold in their aging rates and maximum lifespans. Long‐lived mammals appear to possess traits that extend lifespan and healthspan. Genomic analyses have not revealed a single pro‐longevity function that would account for all longevity effects. In contrast, it appears that pro‐longevity mechanisms may be complex traits afforded by connections between metabolism and protein functions that are impossible to predict by genomic approaches alone. Thus, metabolomics and proteomics studies will be required to understand the mechanisms of longevity. Several examples are reviewed that demonstrate the naked mole rat (NMR) shows unique proteomic signatures that contribute to longevity by overcoming several hallmarks of aging. SIRT6 is also discussed as an example of a protein that evolves enhanced enzymatic function in long‐lived species. Finally, it is shown that several longevity‐related proteins such as Cip1/p21, FOXO3, TOP2A, AKT1, RICTOR, INSR, and SIRT6 harbor posttranslational modification (PTM) sites that preferentially appear in either short‐ or long‐lived species and provide examples of crosstalk between PTM sites. Prospects of enhancing lifespan and healthspan of humans by altering metabolism and proteoforms with drugs that mimic changes observed in long‐lived species are discussed.

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Section: Longevity‐specific Ptm Sites?mentioning

confidence: 99%

Proteomics of Long‐Lived Mammals

et al. 2020

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“…Post-translational modifications (PTMs) represent a form of protein sequence variation in which the intrinsic properties of amino acids in synthesized proteins are altered via chemical modification. Recently, information derived from multiple centralized PTM resources, as well as individual studies, have been combined into a single database describing a broad range of PTM sites across the human proteome [44]. PTMs could directly affect protein aggregation by increasing or decreasing inherent aggregation propensity.…”

Section: A Survey Of Post-translational Modifications Within Human Prldsmentioning

confidence: 99%

“…The ActiveDriver database [44] is a centralized resource containing downloadable and computationally accessible information regarding "high-confidence" protein isoforms, post-translational modification sites, and disease associated mutations in human proteins. We first examined whether alternative splicing would affect predicted aggregation propensity for isoforms that map to a common gene.…”

Section: Alternative Splicing Introduces Sequence Variation That Affementioning

confidence: 99%

Natural and pathogenic protein sequence variation affecting prion-like domains within and across human proteomes

Cascarina

Ross

2020

BMC Genomics

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Background: Impaired proteostatic regulation of proteins with prion-like domains (PrLDs) is associated with a variety of human diseases including neurodegenerative disorders, myopathies, and certain forms of cancer. For many of these disorders, current models suggest a prion-like molecular mechanism of disease, whereby proteins aggregate and spread to neighboring cells in an infectious manner. The development of prion prediction algorithms has facilitated the large-scale identification of PrLDs among "reference" proteomes for various organisms. However, the degree to which intraspecies protein sequence diversity influences predicted prion propensity has not been systematically examined. Results: Here, we explore protein sequence variation introduced at genetic, post-transcriptional, and posttranslational levels, and its influence on predicted aggregation propensity for human PrLDs. We find that sequence variation is relatively common among PrLDs and in some cases can result in relatively large differences in predicted prion propensity. Sequence variation introduced at the post-transcriptional level (via alternative splicing) also commonly affects predicted aggregation propensity, often by direct inclusion or exclusion of a PrLD. Finally, analysis of a database of sequence variants associated with human disease reveals a number of mutations within PrLDs that are predicted to increase prion propensity. Conclusions: Our analyses expand the list of candidate human PrLDs, quantitatively estimate the effects of sequence variation on the aggregation propensity of PrLDs, and suggest the involvement of prion-like mechanisms in additional human diseases.

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“…PTMs frequently correlate with the rate and severity of diseases regardless of whether they are causative or not. For instance, an analysis of disease associated amino acid substitutions revealed approximately 21% of which are located at PTM sites . Furthermore, abnormal phosphorylation of proteins is known to be a cause of cancer, diabetes, and rheumatoid arthritis .…”

Section: Introductionmentioning

confidence: 99%

Engineering Proteases for Mass Spectrometry‐Based Post Translational Modification Analyses

Tran

2018

Proteomics

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Protein post‐translational modifications (PTMs) are important modulators of virtually all cellular processes, and frequently correlate with not only the rate but also severity of diseases. There has been considerable interest to map all possible PTM sites to be used as drug targets. Current approaches for PTM analysis suffer from a number of challenges; one of which is the lack of a PTM specific cleaving reagent. A central technology for global quantitative PTM analysis, mass spectrometry (MS) based proteomics, is biased toward trypsin due to its high activity and specificity. This bias becomes a problem when a PTM is located at or near tryptic cleavage sites, in which case the PTM might block recognition by trypsin, resulting in missed cleavage and sequence coverage gaps. Reviewed here are recent advances in engineering new proteases for PTM analyses, and how these new proteases are beginning to address current challenges in the field.

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ActiveDriverDB: human disease mutations and genome variation in post-translational modification sites of proteins

Cited by 85 publications

References 70 publications

Proteomics of Long‐Lived Mammals

Proteomics of Long‐Lived Mammals

Natural and pathogenic protein sequence variation affecting prion-like domains within and across human proteomes

Engineering Proteases for Mass Spectrometry‐Based Post Translational Modification Analyses

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