scholarly journals ActiveDriverDB: Interpreting Genetic Variation in Human and Cancer Genomes Using Post-translational Modification Sites and Signaling Networks (2021 Update)

2021 ◽  
Vol 9 ◽  
Author(s):  
Michal Krassowski ◽  
Diogo Pellegrina ◽  
Miles W. Mee ◽  
Amelie Fradet-Turcotte ◽  
Mamatha Bhat ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Amino Acid ◽  
Human Population ◽  
Signaling Networks ◽  
Amino Acid Substitutions ◽  
Inherited Disease ◽  
Post Translational Modification ◽  
Functional Impact ◽  
Disease Mutations ◽  
Cancer Genomes

Deciphering the functional impact of genetic variation is required to understand phenotypic diversity and the molecular mechanisms of inherited disease and cancer. While millions of genetic variants are now mapped in genome sequencing projects, distinguishing functional variants remains a major challenge. Protein-coding variation can be interpreted using post-translational modification (PTM) sites that are core components of cellular signaling networks controlling molecular processes and pathways. ActiveDriverDB is an interactive proteo-genomics database that uses more than 260,000 experimentally detected PTM sites to predict the functional impact of genetic variation in disease, cancer and the human population. Using machine learning tools, we prioritize proteins and pathways with enriched PTM-specific amino acid substitutions that potentially rewire signaling networks via induced or disrupted short linear motifs of kinase binding. We then map these effects to site-specific protein interaction networks and drug targets. In the 2021 update, we increased the PTM datasets by nearly 50%, included glycosylation, sumoylation and succinylation as new types of PTMs, and updated the workflows to interpret inherited disease mutations. We added a recent phosphoproteomics dataset reflecting the cellular response to SARS-CoV-2 to predict the impact of human genetic variation on COVID-19 infection and disease course. Overall, we estimate that 16-21% of known amino acid substitutions affect PTM sites among pathogenic disease mutations, somatic mutations in cancer genomes and germline variants in the human population. These data underline the potential of interpreting genetic variation through the lens of PTMs and signaling networks. The open-source database is freely available at www.ActiveDriverDB.org.

scholarly journals Evolutionary and functional lessons from human-specific amino acid substitution matrices

2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Tair Shauli ◽  
Nadav Brandes ◽  
Michal Linial
Keyword(s):  
Genetic Variation ◽  
Amino Acid ◽  
Human Genetic Variation ◽  
Post Translational Modification ◽  
Functional Protein ◽  
Homologous Proteins ◽  
Specific Amino Acid ◽  
Coding Regions ◽  
Substitution Matrices ◽  
Human Specific

Abstract Human genetic variation in coding regions is fundamental to the study of protein structure and function. Most methods for interpreting missense variants consider substitution measures derived from homologous proteins across different species. In this study, we introduce human-specific amino acid (AA) substitution matrices that are based on genetic variations in the modern human population. We analyzed the frequencies of >4.8M single nucleotide variants (SNVs) at codon and AA resolution and compiled human-centric substitution matrices that are fundamentally different from classic cross-species matrices (e.g. BLOSUM, PAM). Our matrices are asymmetric, with some AA replacements showing significant directional preference. Moreover, these AA matrices are only partly predicted by nucleotide substitution rates. We further test the utility of our matrices in exposing functional signals of experimentally-validated protein annotations. A significant reduction in AA transition frequencies was observed across nine post-translational modification (PTM) types and four ion-binding sites. Our results propose a purifying selection signal in the human proteome across a diverse set of functional protein annotations and provide an empirical baseline for interpreting human genetic variation in coding regions.

scholarly journals Asparagine Hydroxylation is a Reversible Post-translational Modification

2020 ◽  
Vol 19 (11) ◽  
pp. 1777-1789 ◽  
Author(s):  
Javier Rodriguez ◽  
Cameron D. Haydinger ◽  
Daniel J. Peet ◽  
Lan K. Nguyen ◽  
Alex von Kriegsheim
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Functional Group ◽  
Signaling Networks ◽  
Post Translational Modification ◽  
Present Evidence ◽  
Intact Proteins ◽  
Acid Hydroxylation ◽  
Cellular Machinery

Amino acid hydroxylation is a common post-translational modification, which generally regulates protein interactions or adds a functional group that can be further modified. Such hydroxylation is currently considered irreversible, necessitating the degradation and re-synthesis of the entire protein to reset the modification. Here we present evidence that the cellular machinery can reverse FIH-mediated asparagine hydroxylation on intact proteins. These data suggest that asparagine hydroxylation is a flexible and dynamic post-translational modification akin to modifications involved in regulating signaling networks, such as phosphorylation, methylation and ubiquitylation.

In Silico Evaluation of Acetylation Mimics in the 27 Lysine Residues of Human Tau Protein

2019 ◽  
Vol 16 (5) ◽  
pp. 379-387 ◽  
Author(s):  
Yong-Chan Kim ◽  
Byung-Hoon Jeong
Keyword(s):  
Amino Acid ◽  
Tau Protein ◽  
In Silico ◽  
Tau Proteins ◽  
Amino Acid Substitutions ◽  
Amyloid Formation ◽  
Post Translational Modification ◽  
Protein Residues ◽  
Lysine Residues ◽  
Acetylation State

Background: Various neurodegenerative diseases, including Alzheimer's disease (AD), are related to abnormal hyperphosphorylated microtubule-associated protein tau accumulation in brain lesions. Recent studies have focused on toxicity caused by another post-translational modification (PTM), acetylation of the lysine (K) residues of tau protein. Because there are numerous acetylation sites, several studies have introduced mimics of tau acetylation using amino acid substitutions from lysine to glutamine (Q). However, human tau protein contains over 20 acetylation sites; thus, investigation of the effects of an acetylated tau is difficult. Objective: Here, the authors in silico evaluated acetylation effects using SIFT, PolyPhen-2 and PROVEAN which can estimate the effects of amino acid substitutions based on the sequence homology or protein structure in tau isoforms. In addition, they also investigated 27 acetylation effects on the amyloid formation of tau proteins using Waltz. Results: 15 acetylation mimics were estimated to be the most detrimental, which indicates that there may be novel pathogenic acetylation sites in the human tau protein. Interestingly, the deleterious effect of acetylation mimics was different according to the type of isoforms. Furthermore, all acetylation mimics were predicted to be a region of amyloid formation at the codons 274-279 of human tau protein. Notably, acetylation mimic of codon 311 (K311Q) induced the formation of an additional amyloid region located on codons 306-311 of the human tau protein. Conclusion: To the best of our knowledge, this is the first simultaneous in-silico evaluation of the acetylation state of 27 human tau protein residues.

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

2017 ◽  
Author(s):  
Michal Krassowski ◽  
Marta Paczkowska ◽  
Kim Cullion ◽  
Tina Huang ◽  
Irakli Dzneladze ◽  
...  
Keyword(s):  
Protein Function ◽  
Molecular Mechanisms ◽  
Application Programming Interface ◽  
The Cancer Genome Atlas ◽  
Disease Genes ◽  
Sequence Motifs ◽  
Inherited Disease ◽  
Post Translational Modification ◽  
Single Nucleotide Variants ◽  
Disease Mutations

AbstractInterpretation of genetic variation is required for understanding genotype-phenotype associations, mechanisms of inherited disease, and drivers of cancer. Millions of single nucleotide variants (SNVs) in human genomes are known and thousands are associated with disease. An estimated 20% of disease-associated missense SNVs are located in protein sites of post-translational modifications (PTMs), chemical modifications of amino acids that extend protein function. ActiveDriverDB is a comprehensive human proteo-genomics database that annotates disease mutations and population variants using PTMs. We integrated >385,000 published PTM sites with ∼3.8 million missense SNVs from The Cancer Genome Atlas (TCGA), the ClinVar database of disease genes, and inter-individual variation from human genome sequencing projects. The database includes interaction networks of proteins, upstream enzymes such as kinases, and drugs targeting these enzymes. We also predicted network-rewiring impact of mutations by analyzing gains and losses of kinase-bound sequence motifs. ActiveDriverDB provides detailed visualization, filtering, browsing and searching options for studying PTM-associated SNVs. Users can upload mutation datasets interactively and use our application programming interface for pipelines. Integrative analysis of SNVs and PTMs helps decipher molecular mechanisms of phenotypes and disease, as exemplified by case studies of disease genes TP53, BRCA2 and VHL. The open-source database is available at https://www.ActiveDriverDB.org.

Recombinant Variants of Tissue-Type Plasminogen Activator Containing Amino Acid Substitutions in the Finger Domain

1992 ◽  
Vol 68 (06) ◽  
pp. 672-677 ◽  
Author(s):  
Hitoshi Yahara ◽  
Keiji Matsumoto ◽  
Hiroyuki Maruyama ◽  
Tetsuya Nagaoka ◽  
Yasuhiro Ikenaka ◽  
...  
Keyword(s):  
Amino Acid ◽  
Plasminogen Activator ◽  
Half Life ◽  
Tissue Type ◽  
Clot Lysis ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Plasma Clot ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryTissue-type plasminogen activator (t-PA) is a fibrin-specific agent which has been used to treat acute myocardial infarction. In an attempt to clarify the determinants for its rapid clearance in vivo and high affinity for fibrin clots, we produced five variants containing amino acid substitutions in the finger domain, at amino acid residues 7–9, 10–14, 15–19, 28–33, and 37–42. All the variants had a prolonged half-life and a decreased affinity for fibrin of various degrees. The 37–42 variant demonstrated about a 6-fold longer half-life with a lower affinity for fibrin. Human plasma clot lysis assay estimated the fibrinolytic activity of the 37–42 variant to be 1.4-fold less effective than that of the wild-type rt-PA. In a rabbit jugular vein clot lysis model, doses of 1.0 and 0.15 mg/kg were required for about 70% lysis in the wild-type and 37–42 variant, respectively. Fibrinogen was degraded only when the wild-type rt-PA was administered at a dose of 1.0 mg/kg. These findings suggest that the 37–42 variant can be employed at a lower dosage and that it is a more fibrin-specific thrombolytic agent than the wild-type rt-PA.

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