scholarly journals Molecular phylogeny and missense mutations of envelope proteins across coronaviruses

2020 ◽  
Author(s):  
Sk Sarif Hassan ◽  
Pabitra Pal Choudhury ◽  
Bidyut Roy
Keyword(s):  
Amino Acids ◽  
Phylogenetic Analysis ◽  
Amino Acid ◽  
Molecular Phylogeny ◽  
Envelope Protein ◽  
Envelope Proteins ◽  
Parental Origin ◽  
Missense Mutations ◽  
E Proteins ◽  
Complete Genomes

Envelope protein is one of the structural viroporins (76–109 amino acids) present in the coronavirus. Sixteen sequentially different E proteins were observed from a total of 4917 available complete genomes as on 18th June, 2020 in the NCBI database. The missense mutations over the envelope protein across various coronaviruses of the $\beta$-genus were analyzed to know the immediate parental origin of the envelope protein of SARS-CoV2. The evolutionary origin is also endorsed by the phylogenetic analysis of the envelope proteins comparing sequence homology as well as amino acid conservations.

scholarly journals The key amino acids of E protein involved in early flavivirus infection: viral entry

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Tao Hu ◽  
Zhen Wu ◽  
Shaoxiong Wu ◽  
Shun Chen ◽  
Anchun Cheng
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Viral Entry ◽  
Envelope Protein ◽  
Cell Attachment ◽  
Envelope Proteins ◽  
Infection Process ◽  
Early Infection ◽  
Protein Amino Acids ◽  
Α Helix

AbstractFlaviviruses are enveloped viruses that infect multiple hosts. Envelope proteins are the outermost proteins in the structure of flaviviruses and mediate viral infection. Studies indicate that flaviviruses mainly use envelope proteins to bind to cell attachment receptors and endocytic receptors for the entry step. Here, we present current findings regarding key envelope protein amino acids that participate in the flavivirus early infection process. Among these sites, most are located in special positions of the protein structure, such as the α-helix in the stem region and the hinge region between domains I and II, motifs that potentially affect the interaction between different domains. Some of these sites are located in positions involved in conformational changes in envelope proteins. In summary, we summarize and discuss the key envelope protein residues that affect the entry process of flaviviruses, including the process of their discovery and the mechanisms that affect early infection.

scholarly journals Phylogenetic analysis and predicted functional effect of protein mutations of E6 and E7 HPV16 strains isolated in Indonesia

2015 ◽  
Vol 24 (4) ◽  
pp. 197-205
Author(s):  
Dwi Wulandari ◽  
Lisnawati Rachmadi ◽  
Tjahjani M. Sudiro
Keyword(s):  
Amino Acids ◽  
Phylogenetic Analysis ◽  
Amino Acid ◽  
Asian American ◽  
Protein Function ◽  
Single Amino Acid ◽  
Hpv16 E6 ◽  
E6 And E7 ◽  
Neutral Mutations

Background: E6 and E7 are oncoproteins of HPV16. Natural amino acid variation in HPV16 E6 can alter its carcinogenic potential. The aim of this study was to analyze phylogenetically E6 and E7 genes and proteins of HPV16 from Indonesia and predict the effects of single amino acid substitution on protein function. This analysis could be used to reduce time, effort, and research cost as initial screening in selection of protein or isolates to be tested in vitro or in vivo.Methods: In this study, E6 and E7 gene sequences were obtained from 12 samples of  Indonesian isolates, which  were compared with HPV16R (prototype) and 6 standard isolates in the category of European (E), Asian (As), Asian-American (AA), African-1 (Af-1), African-2 (Af-2), and North American (NA) branch from Genbank. Bioedit v.7.0.0 was used to analyze the composition and substitution of single amino acids. Phylogenetic analysis of E6 and E7 genes and proteins was performed using Clustal X (1.81) and NJPLOT softwares. Effects of single amino acid substitutions on protein function of E6 and E7 were analysed by SNAP.Results: Java variants and isolate ui66* belonged to European branch, while the others belonged to Asian and African branches. Twelve changes of amino acids were found in E6 and one in E7 proteins. SNAP analysis showed two non neutral mutations, i.e. R10I and C63G in E6 proteins. R10I mutations were found in Af-2 genotype (AF472509) and Indonesian isolates (Af2*), while C63G mutation was found only in Af2*.Conclusion: E6 proteins of HPV16 variants were more variable than E7. SNAP analysis showed that only E6 protein of African-2 branch had functional differences compared to HPV16R.

scholarly journals A Region of the Sir1 Protein Dedicated to Recognition of a Silencer and Required for Interaction with the Orc1 Protein in Saccharomyces cerevisiae

Genetics ◽  
1999 ◽  
Vol 151 (1) ◽  
pp. 31-44 ◽  
Author(s):  
Kelly A Gardner ◽  
Jasper Rine ◽  
Catherine A Fox
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Amino Acids ◽  
Amino Acid ◽  
Origin Recognition Complex ◽  
Dna Binding Domain ◽  
Missense Mutations ◽  
Macromolecular Complexes ◽  
Sequence Elements ◽  
Per Se ◽  
Amino Acid Segment

AbstractSilencing of the cryptic mating-type loci HMR and HML requires the recognition of DNA sequence elements called silencers by the Sir1p, one of four proteins dedicated to the assembly of silenced chromatin in Saccharomyces cerevisiae. The Sir1p is thought to recognize silencers indirectly through interactions with proteins that bind the silencer DNA directly, such as the origin recognition complex (ORC). Eight recessive alleles of SIR1 were discovered that encode mutant Sir1 proteins specifically defective in their ability to recognize the HMR-E silencer. The eight missense mutations all map within a 17-amino-acid segment of Sir1p, and this segment was also required for Sir1p's interaction with Orc1p. The mutant Sir1 proteins could function in silencing if tethered to a silencer directly through a heterologous DNA-binding domain. Thus the amino acids identified are required for Sir1 protein's recognition of the HMR-E silencer and interaction with Orc1p, but not for its ability to function in silencing per se. The approach used to find these mutations may be applicable to defining interaction surfaces on proteins involved in other processes that require the assembly of macromolecular complexes.

scholarly journals Abstract P-33: Structural Basis for the Growing Microtubule End Recognition by End Binding Proteins

2021 ◽  
Vol 11 (Suppl_1) ◽  
pp. S26-S26
Author(s):  
Alena Korshunova
Keyword(s):  
Amino Acids ◽  
Phylogenetic Analysis ◽  
Amino Acid ◽  
Molecular Mechanism ◽  
Binding Proteins ◽  
Dynamic Instability ◽  
3D Structure ◽  
Structural Basis ◽  
Microtubule Dynamic ◽  
Gtp Hydrolysis

Background: Eukaryotic end binding proteins (EBs) can follow the growing microtubule end. EBs play a crucial role in microtubule dynamic instability and promote simultaneously growth rate and catastrophe frequency. It makes EB-like proteins perspective drag targets for a wide number of diseases. But the molecular mechanism of tip tracking by EB-like proteins remains unknown. Studies of mutants have revealed that the conservative amino acid Q102 (numbering relative to the human EB1 protein) plays a key role in the recognition of the growing microtubule end. However, the 3D structure studies revealed that this amino acid has no bonds with tubulin. In this work, we performed structural and phylogenetic analysis of EBs proteins to identify a possible molecular mechanism behind the plus end tracking. Methods: UCSF Chimera10 was used for structural analysis. Phylogenetic analysis was performed with MEGA X software. 3D structures of EBs and microtubules with different states of GTP hydrolysis were used (pdb 3JAK, 3JAS, 3JAT, 3JAW, 3JAL, 3JAR, 6DPU, 6DPV, 6DPW). Results: We have shown that two conservative amino acids (K100, E106) should play an important role in the recognition of the microtubule plus end in addition to Q102. It was concluded that these amino acids together form the plus-end «navigation site» of EBs. Analysis of possible interaction of the «navigation site» amino acids with microtubules in different conformational states suggested that the main mechanism of growing microtubule end recognition is not due to an affinity increase for a certain state of tubulin in microtubules at their end, but it due to a significant affinity decrease in other parts of the microtubule as a result of steric clashes. Conclusion: Thus, the results of the analysis suggested the possible molecular mechanism that provides the tip tracking by EB-like proteins and allowed us to identify the key amino acids of this mechanism.

scholarly journals A Numerical Representation and Classification of Codons to Investigate Codon Alternation Patterns during Genetic Mutations on Disease Pathogenesis

2020 ◽  
Author(s):  
Antara Sengupta ◽  
Pabitra Pal Choudhury ◽  
Subhadip Chakraborty ◽  
Swarup Roy ◽  
Jayanta Kumar Das ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Chemical Properties ◽  
Numerical Representation ◽  
Missense Mutations ◽  
Disease Pathogenesis ◽  
Physical Density ◽  
Monogenic Diseases

Motivation: Alteration of amino acid is possible due to mutation in codons that could have a potential impact in a diseased condition. Effective mutation analysis can help to predict the fate of the diseased individual which can be validated later by in-vitro experimentations. It may also help an individual who is asymptomatic but having a particular genetic change for early detection and diagnosis during any terminal diseases. We try to investigate the codon alteration patterns and its impact during mutation for the genes known to be responsible for a particular disease.Results: For our current study, we consider neurodegenerative and monogenic diseases. We use numerical representation based on a determinative degree and classification of codons as well as amino acids into three different classes (Strong, Weak and Transition) for the analysis. Our analysis reveals that the strong class codons are highly mutated followed by weak and transition class. We observe that most of the mutations occur in the first or second positions in the codon rather than the third. While looking into the chemical properties of amino acid, we observe that amino acids belong to the aliphatic group are affected most during missense mutations. Our investigation further emphasises that in most of the cases the change in the determinative degree of codon due to mutation is directly proportional to the physical density property. In addition, our scheme gives a more microscopic and alternative representation of the existing codon table that helps in deciphering interesting codon alteration patterns during mutations in disease pathogenesis.

scholarly journals Structural Analysis of Four Newly Identified Extracellular Membrane-Proximal Missense Mutations in Patients with Glanzmann Thrombasthenia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1452-1452
Author(s):  
Xavier Pillois ◽  
Mathieu Fiore ◽  
Alan Nurden
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Conflicts Of Interest ◽  
Severe Bleeding ◽  
Type I ◽  
Missense Mutations ◽  
Glanzmann Thrombasthenia ◽  
Activated State ◽  
Platelet Disorder ◽  
Β Sheets

Abstract Background: Glanzmann thrombasthenia (GT), an autosomal recessive inherited platelet disorder, is a moderate to severe bleeding syndrome caused by the absence of platelet aggregation due to quantitative and/or qualitative deficiencies of the αIIbβ3 integrin. We recently identified 41 causative missense mutations of which 24 were novel in a large cohort of 76 GT families (Genoscope project). These mutations mainly localize to the headpiece region of the integrin that has been well studied but 4 mutations although extracellular were proximal to the plasma membrane. We therefore performed molecular modeling of these 4 mutations to obtain new insights into the structure of a poorly understood region of this unique receptor. Aim: To identify structures or conformations engaged in the stability of the integrin and which are important for maturation and expression. Results: Of the 4 novel selected mutations, 3 concerned the calf-2 domain of αIIb - Gly792Glu (G823E, nomenclature with leader sequence), Leu924Gln (L955Q) and Thr953Lys (T984K) and one the EGF-3 domain of β3 Gly540Asp (G566D). All of these mutations affected highly conserved amino acids and were predicted to be damaging by in silico analysis (SIFT, Polyphen). None influenced glycosylation or mRNA splicing. They were present either in a homozygous form (β3 G540D) or were heterozygous in association with an identified and proven null mutation. Three were associated with type I GT (<5% αIIbβ3), while the αIIbG792E mutation occurred in a patient with type II GT (with 10% residual αIIbβ3) whose much reduced but partial transport to the surface was confirmed following expression of the recombinant integrin in CHO cells (with pro-αIIb predominating in the cytoplasm). The structural implications of these amino acid substitutions was assessed using PyMol Molecular Graphics System version 1.3 (www.pymol.org) based on the crystallographic data of αIIbβ3 in the bent non-activated state (3fcs PDB file). Amino acids were visualized in the rotamer form showing side change orientations incorporated from the Dunbrack Backbone library with the maximum probability. We first determined that the αIIb calf-2 domain has a β barrel-like structure largely composed of hydrophobic amino acids whose side chains orientate towards the inner cavity. Interestingly, L924Q and T953K substitutions occur at or adjacent to a conserved motif consisting of five polar amino acids central to the β barrel protected from H2O molecules and involved in H-bond interactions. This particular motif, specific to calf-2, may introduce rigidity close to the membrane. Both L924Q and T953K disrupt the β barrel motif and promote flexibility. G792E is situated between the calf-1 and calf-2 domains in an unstructured connecting loop between two adjacent β sheets. Its replacement by the larger negatively charged Glu introduces steric encumbrance and results in an increase of the angle formed by the two calf domains, probably leading to the straightening of the second distal part of the long arm of αIIb. The β3 G540D substitution is found in the EGF3 domain of β3 that occurs at the axe of the cysteine-rich domain of the β3 arm, facing the αIIb calf-1 and calf-2 domains in the intact integrin. This substitution with the introduction of a charged and larger amino acid results in a weaker link between the two β sheets of EGF-3 and a loss of H-bonds. The result is an increased fragility within the β3 arm structure notably at the site of two stacked aromatic amino acids (H539 and W553) with a moving apart of the β sheets. Conclusions: We show that 4 novel missense mutations in the extracellular membrane-proximal domains of αIIb and β3 cause conformational changes in domains that control the overall structure of the newly formed integrin. They show how the structure of both domains is under tight quality control and that precisely defined conformations are indispensable for αIIbβ3 maturation. Disclosures No relevant conflicts of interest to declare.

44-amino-acid E5 transforming protein of bovine papillomavirus requires a hydrophobic core and specific carboxyl-terminal amino acids

1988 ◽  
Vol 8 (10) ◽  
pp. 4071-4078
Author(s):  
B H Horwitz ◽  
A L Burkhardt ◽  
R Schlegel ◽  
D DiMaio
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Saturation Mutagenesis ◽  
Amino Acid Substitutions ◽  
Bovine Papillomavirus ◽  
Missense Mutations ◽  
Focus Formation ◽  
E5 Protein ◽  
Transforming Activity ◽  
Carboxyl Terminal

The 44-amino-acid E5 protein of bovine papillomavirus type 1 is the shortest known protein with transforming activity. To identify the specific amino acids required for in vitro focus formation in mouse C127 cells, we used oligonucleotide-directed saturation mutagenesis to construct an extensive collection of mutants with missense mutations in the E5 gene. Characterization of mutants with amino acid substitutions in the hydrophobic middle third of the E5 protein indicated that efficient transformation requires a stretch of hydrophobic amino acids but not a specific amino acid sequence in this portion of the protein. Many amino acids in the carboxyl-terminal third of the protein can also undergo substitution without impairment of focus-forming activity, but the amino acids at seven positions, including two cysteine residues that mediate dimer formation, appear essential for efficient transforming activity. These essential amino acids are the most well conserved among related fibropapillomaviruses. The small size of the E5 protein, its lack of similarity to other transforming proteins, and its ability to tolerate many amino acid substitutions implies that it transforms cells via a novel mechanism.

scholarly journals Principal neutralizing domain of the human immunodeficiency virus type 1 envelope protein

1989 ◽  
Vol 86 (17) ◽  
pp. 6768-6772 ◽  
Author(s):  
K Javaherian ◽  
A J Langlois ◽  
C McDanal ◽  
K L Ross ◽  
L I Eckler ◽  
...  
Keyword(s):  
Amino Acids ◽  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Protein ◽  
Neutralizing Antibodies ◽  
Immunodeficiency Virus ◽  
Hiv 1

The principal neutralizing determinant of human immunodeficiency virus type 1 (HIV-1) is located in the external envelope protein, gp120, and has previously been mapped to a 24-amino acid-long sequence (denoted RP135). We show here that deletion of this sequence renders the envelope unable to elicit neutralizing antibodies. In addition, using synthetic peptide fragments of RP135, we have mapped the neutralizing determinant to 8 amino acids and found that a peptide of this size elicits neutralizing antibodies. This sequence contains a central Gly-Pro-Gly that is generally conserved between different HIV-1 isolates and is flanked by amino acids that differ from isolate to isolate. Antibodies elicited by peptides from one isolate do not neutralize two different isolates, and a hybrid peptide, consisting of amino acid sequences from two isolates, elicits neutralizing antibodies to both isolates. By using a mixture of peptides of this domain or a mixture of such hybrid peptides the type-specificity of the neutralizing antibody response to this determinant can perhaps be overcome.

scholarly journals Retention and Loss of Amino Acid Biosynthetic Pathways Based on Analysis of Whole-Genome Sequences

2006 ◽  
Vol 5 (2) ◽  
pp. 272-276 ◽  
Author(s):  
Samuel H. Payne ◽  
William F. Loomis
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Minimal Medium ◽  
Whole Genome ◽  
Biosynthetic Pathways ◽  
Genome Sequences ◽  
Whole Genomes ◽  
Complete Genomes ◽  
Computational Analyses

ABSTRACT Plants and fungi can synthesize each of the 20 amino acids by using biosynthetic pathways inherited from their bacterial ancestors. However, the ability to synthesize nine amino acids (Phe, Trp, Ile, Leu, Val, Lys, His, Thr, and Met) was lost in a wide variety of eukaryotes that evolved the ability to feed on other organisms. Since the biosynthetic pathways and their respective enzymes are well characterized, orthologs can be recognized in whole genomes to understand when in evolution pathways were lost. The pattern of pathway loss and retention was analyzed in the complete genomes of three early-diverging protist parasites, the amoeba Dictyostelium, and six animals. The nine pathways were lost independently in animals, Dictyostelium, Leishmania, Plasmodium, and Cryptosporidium. Seven additional pathways appear to have been lost in one or another parasite, demonstrating that they are dispensable in a nutrition-rich environment. Our predictions of pathways retained and pathways lost based on computational analyses of whole genomes are validated by minimal-medium studies with mammals, fish, worms, and Dictyostelium. The apparent selective advantages of retaining biosynthetic capabilities for amino acids available in the diet are considered.

scholarly journals Predicting the phenotype of Mendelian disease missense mutations using amino acid conservation and protein stability change

2016 ◽  
Author(s):  
Maria T. Chavez ◽  
Ethan O. Perlstein
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protein Stability ◽  
Model Organisms ◽  
Mendelian Disease ◽  
Missense Mutations ◽  
Lysosomal Storage ◽  
Mendelian Diseases ◽  
Stability Change ◽  
Jensen Shannon Divergence

AbstractMany Mendelian diseases are caused by recessive, loss-of-function missense mutations. On a gene-by-gene basis, it has been demonstrated that missense mutations cause, among other defects, protein misfolding, protein instability, protein mistransport, which strongly suggests that pathogenic missense mutations do not occur at random positions. Based on those observations, we predicted that Mendelian disease missense mutations are enriched in evolutionarily-conserved amino acids. In a pilot set of 260 Mendelian diseases genes affecting cellular organelles we show that missense mutations indeed occur in amino acids that are significantly more conserved than the average amino acid in the protein based on three different scoring methods (Jensen Shannon Divergence p = 7.78E-03, Shannon Entropy p = 1.68E-13, Sum of Pairs p = 1.55E-17). In order to understand how these results might be related to clinical phenotypes in humans or preclinical phenotypes in model organisms, we calculated the protein stability change upon mutation (ΔΔGu) using EASE-MM and found that, on average, pathogenic mutations cause a stability change of greater magnitude than benign mutations (p = 4.414428E-23). Finally, we performed a computational case study on NPC1, the gene responsible for 95% of diagnosed cases of the lysosomal storage disorder Niemann-Pick Type C using a set of 411 missense mutations from the Exome Aggregation Consortium.

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