Predicting the Effects of Amino Acid Substitutions on Protein Function

2006 ◽  
Vol 7 (1) ◽  
pp. 61-80 ◽  
Author(s):  
Pauline C. Ng ◽  
Steven Henikoff
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Amino Acid Substitutions

scholarly journals Understanding the origins of loss of protein function by analyzing the effects of thousands of variants on activity and abundance

2020 ◽  
Author(s):  
Matteo Cagiada ◽  
Kristoffer E. Johansson ◽  
Audronė Valančiūtė ◽  
Sofie V. Nielsen ◽  
Rasmus Hartmann-Petersen ◽  
...  
Keyword(s):  
Experimental Data ◽  
Amino Acid ◽  
Enzymatic Activity ◽  
Indirect Effects ◽  
Protein Function ◽  
Evolutionary Conservation ◽  
Amino Acid Substitutions ◽  
Loss Of Function ◽  
Basic Understanding ◽  
Computational Analyses

AbstractUnderstanding and predicting how amino acid substitutions affect proteins is key to practical uses of proteins, and to our basic understanding of protein function and evolution. Amino acid changes may affect protein function in a number of ways including direct perturbations of activity or indirect effects on protein folding and stability. We have analysed 6749 experimentally determined variant effects from multiplexed assays on abundance and activity in two proteins (NUDT15 and PTEN) to quantify these effects, and find that a third of the variants cause loss of function, and about half of loss-of-function variants also have low cellular abundance. We analyse the structural and mechanistic origins of loss of function, and use the experimental data to find residues important for enzymatic activity. We performed computational analyses of protein stability and evolutionary conservation and show how we may predict positions where variants cause loss of activity or abundance.

scholarly journals Analysis of convergent and parallel amino acid substitutions in the HSP90AA1 gene among high-elevation anurans

SURG Journal ◽  
2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Joyce Tao
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Structural Damage ◽  
Molecular Mechanisms ◽  
Cold Water ◽  
High Elevation ◽  
Structure Stability ◽  
Amino Acid Substitutions ◽  
Stability Change ◽  
Protein Structure Stability

A significant amount of convergent and parallel amino acid substitutions in the HSP90AA1 gene has been detected among four species of high-elevation anurans: Bufo tibetanus, Scutiger boulengeri, Rana kukunoris, and Nanorana parkeri. As HSP proteins are involved in response to environmental stress, it is possible these mutations play a role in high-elevation adaptation. In this study, I investigated the functional consequences of these substitutions and inferred their potential links to adaptation. I examined HSP90AA1 sequences of 13 anuran species previously studied. Using PROVEAN, I isolated three deleterious mutations: P65S, K195A, and _199I, each shared between two of the high-elevation species. I further analyzed the protein structure, stability change, and structural damage using model predictions. Based on its buried location and cavity expansion, P65S was predicted to most likely alter protein function. Furthermore, I examined HSP90AA1 sequences of over 100 other animal species available from public databases and found that serine at site 65 is ubiquitously present in cold-water fish, suggesting the substitution is related to cold adaptation. Alanine at site 195 and isoleucine at site 199 were not found in any other species, but these substitutions also might impact protein function as they are predicted to be destabilizing and their ancestral residues have reported post-translational modifications in orthologs. Tests of protein function and an investigation of more sequences from high-elevation species would help to further link these substitutions to adaptation, particularly P65S. Identifying mutations that contribute to high-elevation adaptation would aid in uncovering the molecular mechanisms of adaptation.

scholarly journals The Use of Orthologous Sequences to Predict the Impact of Amino Acid Substitutions on Protein Function

PLoS Genetics ◽  
2010 ◽  
Vol 6 (5) ◽  
pp. e1000968 ◽  
Author(s):  
Nicholas J. Marini ◽  
Paul D. Thomas ◽  
Jasper Rine
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Amino Acid Substitutions ◽  
The Impact

scholarly journals Application of computational algorithms to assess the functionality of non-synonymous substitutions in MHC DRB gene of Nigerian goats

Genetika ◽  
2017 ◽  
Vol 49 (1) ◽  
pp. 63-76
Author(s):  
Abdulmojeed Yakubu ◽  
Adebowale Salako ◽  
Donato de ◽  
Ikhide Imumorin
Keyword(s):  
Amino Acid ◽  
Mhc Class Ii ◽  
Protein Function ◽  
Gene Families ◽  
Acid Sites ◽  
Amino Acid Substitutions ◽  
Nucleotide Polymorphisms ◽  
Antigen Binding Site ◽  
Exon 2 ◽  
Drb Gene

The Major Histocompatibility Complex (MHC) contains highly variable multi-gene families, which play a key role in the adaptive immune response within vertebrates. Among the Capra MHC class II genes, the expressed DRB locus is highly polymorphic, particularly in exon 2, which encodes the antigen-binding site. Models of variable non-synonymous/synonymous rate ratios among sites may provide important insights into functional constraints at different amino acid sites and may be used to detect sites under positive selection. Many non-synonymous single nucleotide polymorphisms (nsSNPs) at the DRB locus in goats are suspected to impact protein function. This study, therefore, aimed at comparing the efficiency of six computational approaches to predict the likelihood of a particular non-synonymous (amino acid change) coding SNP to cause a functional impact on the protein. This involved the use of PANTHER, SNAP, SIFT, PolyPhen-2, PROVEAN and nsSNPAnalyzer bioinformatics analytical tools in detecting harmful and beneficial effects at H57G, Y89R, V104D and Y112I substitutions in the peptide binding region of the DRB gene of Nigerian goats. The results from PANTHER analysis revealed that H57G, Y89R and Y112I substitutions (Pdeleterious= 0.113, 0.204 and 0.472, respectively) were beneficial; while that of V104D was deleterious (Pdeleterious= 0.756), an indication that it was non-neutral. As regards the SNAP approach, H57G and Y89R substitutions were returned neutral with expected accuracy of 53 and 69%, respectively while V104D and Y112I substitutions were harmful. H57G and Y89R substitutions were also found harmless in the SIFT analysis. However, only H57G (PROVEAN) and V104D (nsSNPAnalyzer) amino acid substitutions were found to be beneficial. Interestingly, the predicted 3D structures of both native and mutant DRB protein appeared similar as validated by Ramachandran plots. The consensus reached by PANTHER, SNAP, SIFT and PolyPhen-2 approaches on the neutrality especially of H57G (PROVEAN inclusive) and Y89R amino acid substitutions may be used in search of disease resistant genotypes at the DRB locus of Nigerian goats.

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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