scholarly journals Amino acid exchangeabilities vary across the tree of life

2019 ◽  
Vol 5 (12) ◽  
pp. eaax3124 ◽  
Author(s):  
Zhengting Zou ◽  
Jianzhi Zhang
Keyword(s):  
Amino Acid ◽  
Maximum Likelihood ◽  
Tree Of Life ◽  
Amino Acid Residues ◽  
Genome Sequences ◽  
Genome Wide ◽  
Evolutionary Changes ◽  
Domains Of Life ◽  
Expected Complexity

Different amino acid pairs have drastically different relative exchangeabilities (REs), and accounting for this variation is an important and common practice in inferring phylogenies, testing selection, and predicting mutational effects, among other analyses. In all such endeavors, REs have been generally considered invariant among species; this assumption, however, has not been scrutinized. Using maximum likelihood to analyze 180 genome sequences, we estimated REs from 90 clades representing all three domains of life, and found numerous instances of substantial between-clade differences in REs. REs show more differences between orthologous proteins of different clades than unrelated proteins of the same clade, suggesting that REs are genome-wide, clade-specific features, probably a result of proteome-wide evolutionary changes in the physicochemical environments of amino acid residues. The discovery of among-clade RE variations cautions against assuming constant REs in various analyses and demonstrates a higher-than-expected complexity in mechanisms of proteome evolution.

scholarly journals Peptidase E, a Peptidase Specific for N-Terminal Aspartic Dipeptides, Is a Serine Hydrolase

2000 ◽  
Vol 182 (9) ◽  
pp. 2536-2543 ◽  
Author(s):  
Rachel A. L. Lassy ◽  
Charles G. Miller
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Site Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Serine Hydrolase ◽  
Genome Sequences ◽  
New Family ◽  
The Family ◽  
Serovar Typhimurium ◽  
Structural Classes

ABSTRACT Salmonella enterica serovar Typhimurium peptidase E (PepE) is an N-terminal Asp-specific dipeptidase. PepE is not inhibited by any of the classical peptidase inhibitors, and its amino acid sequence does not place it in any of the known peptidase structural classes. A comparison of the amino acid sequence of PepE with a number of related sequences has allowed us to define the amino acid residues that are strongly conserved in this family. To ensure the validity of this comparison, we have expressed one of the most distantly related relatives (Xenopus) in Escherichia coli and have shown that it is indeed an Asp-specific dipeptidase with properties very similar to those of serovar Typhimurium PepE. The sequence comparison suggests that PepE is a serine hydrolase. We have used site-directed mutagenesis to change all of the conserved Ser, His, and Asp residues and have found that Ser120, His157, and Asp135 are all required for activity. Conversion of Ser120 to Cys leads to severely reduced (104-fold) but still detectable activity, and this activity but not that of the parent is inhibited by thiol reagents; these results confirm that this residue is likely to be the catalytic nucleophile. These results suggest that PepE is the prototype of a new family of serine peptidases. The phylogenetic distribution of the family is unusual, since representatives are found in eubacteria, an insect (Drosophila), and a vertebrate (Xenopus) but not in the Archaea or in any of the other eukaryotes for which genome sequences are available.

scholarly journals Genome-wide association study of HIV whole genome sequences validated using drug resistance

2016 ◽  
Author(s):  
Robert A. Power ◽  
Siva Davaniah ◽  
Anne Derache ◽  
Eduan Wilkinson ◽  
Frank Tanser ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
High Throughput Sequencing ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genome Sequences ◽  
Gag Protein ◽  
Genome Wide

AbstractGenome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics.We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1st line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naive to the respective treatment.GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we highlighted the ability of GWAS to identify epistatic effects, identifying two replicable variants within amino acid 68 of the reverse transcriptase protein previously described as potential fitness compensatory mutations. A possible additional DR variant within amino acid 91 of the matrix region of the Gag protein was associated with tenofovir failure, highlighting the ability of GWAS to identify variants outside classical candidate genes. Our results also suggest a polygenic component to DR.These results validate the applicability of GWAS to HIV WGS data even in relative small samples, and emphasise how high throughput sequencing can provide novel and clinically relevant insights. Further they suggested that for viruses like HIV, population structure was only minor concern compared to that seen in bacteria or parasite GWAS. Given the small genome length and reduced burden for multiple testing, this makes HIV an ideal candidate for GWAS.

scholarly journals Archaeal Eukaryote-Like Serine/Threonine Protein Kinase Interacts with and Phosphorylates a Forkhead-Associated-Domain-Containing Protein

2010 ◽  
Vol 192 (7) ◽  
pp. 1956-1964 ◽  
Author(s):  
Bin Wang ◽  
Shifan Yang ◽  
Lei Zhang ◽  
Zheng-Guo He
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Structural Model ◽  
Kinase Domain ◽  
Amino Acid Residues ◽  
Fha Domain ◽  
Domains Of Life ◽  
Substrate Phosphorylation

ABSTRACT Protein phosphorylation plays an important role in cell signaling. However, in the Archaea, little is known about which proteins are phosphorylated and which kinases are involved. In this study, we identified, for the first time, a typical eukaryote-like Ser/Thr protein kinase and its protein partner, a forkhead-associated (FHA)-domain-containing protein, from the archaeon Sulfolobus tokodaii strain 7. This protein kinase, ST1565, physically interacted with the FHA-domain-containing protein, ST0829, both in vivo and in vitro. ST1565 preferred Mn2+ as a cofactor for autophosphorylation and for substrate phosphorylation; the optimal temperature for this was 45°C, and the optimal pH was 5.5 to 7.5. The critical amino acid residues of the conserved FHA and kinase domain sites were identified by performing a series of mutation assays. Thr329 was part of a major activation site in the kinase, while Thr326 was a negative regulation site. Several mutants with amino acid substitutions in the conserved FHA domain sites of ST0829 did not physically interact with ST1565. A structural model for the FHA domain demonstrated that the mutation sites were located at the edge of the protein and thus were in the domain that potentially interacts with ST1565. This report describes pioneering work on the third domain of life, the Archaea, showing that a protein kinase interacts with and phosphorylates an FHA-domain-containing protein. Our data provide critical information on the structural or functional characteristics of archaeal proteins and could help increase our understanding of fundamental signaling mechanisms in all three domains of life.

A ribosomally synthesized and post-translationally modified peptide containing a β-amino acid and a macrocyclic motif

2021 ◽  
Author(s):  
Shan Wang ◽  
Qing Fang ◽  
Roland Gyampoh ◽  
Zhou Lu ◽  
Yingli Gao ◽  
...  
Keyword(s):  
Amino Acid ◽  
Computational Modelling ◽  
Genomic Analysis ◽  
Structural Diversity ◽  
Biosynthetic Gene Cluster ◽  
Amino Acid Residues ◽  
Post Translational Modifications ◽  
Gram Positive Bacteria ◽  
Modified Peptides ◽  
Domains Of Life

Abstract Ribosomally synthesized and post-translationally modified peptides (RiPPs) are structurally complex naturally occurring metabolites across all three domains of life. Despite the structural diversity of RiPPs that stems from the extensive post-translational modifications, only α-amino acid residues have been found in known RiPPs. Here we report discovery of a new 27-mer peptide, kintamdin, using comprehensive MS and NMR structural elucidation and genomic analysis together with computational modelling. The peptide features a β-amino acid residue and a new thioether macrocyclic ring. Heterologous expression and gene inactivation allowed the identification of the minimal biosynthetic gene cluster (BGC). The gene products in kin BGC share low homologues compared to other known RiPP pathways, further rendering the novelty of kintamdin. Biochemical analysis indicated that KinO mediate di-methylation reaction to yield kintamidn. Finally, the occurrence of the kin-like BGCs in Gram-positive bacteria suggested the biological importance of this new group of RiPPs.

scholarly journals Genome-wide Mutation Landscape of SARS-CoV-2

2020 ◽  
Author(s):  
Xiaofei Yang ◽  
Li Lv ◽  
Kai Ye
Keyword(s):  
Amino Acid ◽  
Phylogenetic Trees ◽  
Accumulation Rate ◽  
Whole Genome ◽  
Spike Glycoprotein ◽  
Genome Sequences ◽  
Current Spreading ◽  
Genome Wide ◽  
Mutational Hotspots ◽  
Genome Variations

Abstract Background: SARS-CoV-2 has become a pandemic and researchers have built phylogenetic trees to trace the spread of the virus. However, the accumulation rate of variations and mutational hotspots remain largely unclear. Results: We collected more than 3,100 SARS-CoV-2 genome sequences from GISAID and profiled the landscape of whole genome variations. We detected 2,096 single nucleic variants (SNVs) and seven short deletions. 1,224 of them (58.4%) are missenses variation, altering the corresponding residues. We found the accumulation rate of SNVs in the current spreading situation is 6.36e-2/day. We found 15 missenses SNVs are extremely high frequent (existing in more than 100 genome sequences, p < 1e-5), effecting ORF1ab, S, ORF3a, M, ORF8, and N. Moreover, one frequent substitution at locus 23,403 changes the 614th amino acid of spike glycoprotein from D to G, potentially effecting the functions of this key protein. Conclusion: Our study provided the genome-wide mutation landscape of SARS-CoV-2. We found the continent specific mutational patterns and 15 missenses high frequent SNVs effecting 6 genes of the virus, may promoting the adaption of the virus during evolving.

scholarly journals Susceptibility of spike glycoprotein and RNA-dependent RNA polymerase of SARS-CoV-2 to mutation: in silico structural dynamics study

2021 ◽  
Vol 9 (4) ◽  
pp. 148-152
Author(s):  
Toluwase Hezekiah Fatoki ◽  
Jude Akinyelu ◽  
Oluwafijimi Yomi Adetuyi ◽  
Temitope Olawale Jeje ◽  
Uchechukwu Nebo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Rna Polymerase ◽  
In Silico ◽  
Structural Flexibility ◽  
Amino Acid Residues ◽  
Spike Glycoprotein ◽  
Rna Dependent Rna Polymerase ◽  
Evolutionary Changes ◽  
Fast Pace ◽  
Structural Fluctuations

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a microorganism that causes coronavirus disease 2019 (COVID-19). Mutations affect evolutionary conservation of microorganisms. The fast pace evolutionary changes are currently affecting pathogenicity of SARS-CoV-2. In this study, the structural fluctuations of the amino acid residues in the spike glycoprotein and RNA-dependent RNA polymerase (nsp12) of SARS-CoV-2 were investigated by in silico approach using structural flexibility dynamics to decipher susceptibility to mutation. The result of this study implicated key amino acid residues (with rmsf) which could be very susceptible to mutation, which include residues 50 (3.79 Å), 119 (4.56 Å), 120 (3.53 Å), 220 (3.84 Å), 265 (4.31 Å) of RNA-dependent RNA polymerase (nsp12), as well as residues 477 (4.21 Å), 478 (4.82 Å), 479 (5.40 Å), 481 (5.94 Å), 560 (4.63 Å), 704 (4.02 Å), 848 (4.58 Å), 1144 (4.56 Å) and 1147 (4.61 Å) of spike glycoprotein. The SARS-CoV-2 mutations destabilized the overall protein structure in multiples of amino acid residues which could interfere with active site leading to insensitivity or resistance to the inhibitors. Mutation T478K of Spike glycoprotein showed the highest deviation in the structure. Overall, spike glycoprotein has the highest number of mutations, and these variants could increase the risk to human health if not mitigated in the population.

Substrate Recognition by Vitamin K-Dependent Carboxylase

1987 ◽  
Vol 57 (01) ◽  
pp. 017-019 ◽  
Author(s):  
Magda M W Ulrich ◽  
Berry A M Soute ◽  
L Johan M van Haarlem ◽  
Cees Vermeer
Keyword(s):  
Amino Acid ◽  
Vitamin K ◽  
Substrate Recognition ◽  
Bovine Liver ◽  
Amino Acid Residues

SummaryDecarboxylated osteocalcins were prepared and purified from bovine, chicken, human and monkey bones and assayed for their ability to serve as a substrate for vitamin K-dependent carboxylase from bovine liver. Substantial differences were observed, especially between bovine and monkey d-osteocalcin. Since these substrates differ only in their amino acid residues 3 and 4, it seems that these residues play a role in the recognition of a substrate by hepatic carboxylase.

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