scholarly journals Evolutionary Models of Amino Acid Substitutions Based on the Tertiary Structure of their Neighborhoods

2021 ◽  
Author(s):  
Elias Primetis ◽  
Spyridon Chavlis ◽  
Pavlos Pavlidis
Keyword(s):  
Amino Acid ◽  
Tertiary Structure ◽  
Amino Acid Substitutions ◽  
Evolutionary Models

Characterization of Six Mutations in Five Spanish Patients with Mitochondrial Acetoacetyl-CoA Thiolase Deficiency: Effects of Amino Acid Substitutions on Tertiary Structure

2002 ◽  
Vol 75 (3) ◽  
pp. 235-243 ◽  
Author(s):  
Toshiyuki Fukao ◽  
Haruki Nakamura ◽  
Kozue Nakamura ◽  
Celia Perez-Cerda ◽  
Antonio Baldellou ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tertiary Structure ◽  
Amino Acid Substitutions

scholarly journals Evolutionary Models of Amino Acid Substitutions Based on the Tertiary Structure of their Neighborhoods

2018 ◽  
Author(s):  
Elias Primetis ◽  
Spyridon Chavlis ◽  
Pavlos Pavlidis
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Substitution ◽  
Tertiary Structure ◽  
Protein Structures ◽  
Amino Acid Substitutions ◽  
Tertiary Structures ◽  
Substitution Matrices ◽  
Amino Acid Substitution Model ◽  
Amino Acid Substitution Matrices

AbstractIntra-protein residual vicinities depend on the involved amino acids. Energetically favorable vicinities (or interactions) have been preserved during evolution, while unfavorable vicinities have been eliminated. We describe, statistically, the interactions between amino acids using resolved protein structures. Based on the frequency of amino acid interactions, we have devised an amino acid substitution model that implements the following idea: amino acids that have similar neighbors in the protein tertiary structure can replace each other, while substitution is more difficult between amino acids that prefer different spatial neighbors. Using known tertiary structures for α-helical membrane (HM) proteins, we build evolutionary substitution matrices. We constructed maximum likelihood phylogenies using our amino acid substitution matrices and compared them to widely-used methods. Our results suggest that amino acid substitutions are associated with the spatial neighborhoods of amino acid residuals, providing, therefore, insights into the amino acid substitution process.

Hb Dothan [β25/26 (B7/B8)/(-GTG/-GLY)/Gly+Glu→Glu]; A Novel Mechanism Leading to a M-Hemoglobin.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1440-1440
Author(s):  
Ferdane Kutlar ◽  
Lee Hilliard ◽  
Lina Zhuang ◽  
Niren Patel ◽  
Abdullah Kutlar
Keyword(s):  
Amino Acid ◽  
Tertiary Structure ◽  
Globin Gene ◽  
Binding Pocket ◽  
Single Amino Acid ◽  
Structural Abnormality ◽  
Amino Acid Substitutions ◽  
Heme Binding ◽  
Globin Chain ◽  
Nucleotide Deletion

Abstract Hereditary methemoglobinemia is a relatively rare disorder usually manifesting with cyanosis at birth. The more common form results from the deficiency of the enzyme, NADH-Cytochrome b5 reductase (methemoglobin reductase, diaphorase) and displays an autosomal recessive inheritance pattern. Less common are the so-called M-hemoglobins with an autosomal dominant pattern, which result from amino acid substitutions in the heme binding pocket of α, β, or less commonly γ-globin chains. The majority of the M-hemoglobin (Hb) variants occur from substitutions in the E or F-helices, which constitute the heme binding pocket, most commonly from amino acid substitutions involving the conserved proximal (F8) or distal (E11) histidine residues. Here we report a new Hb variant due to a three nucleotide deletion (-GTG between codons 25 and 26 of the β globin gene causing a single amino acid (-Gly) deletion in the B helix (B7/B8) of the β-globin chain that leads to methemoglobinemia with a novel mechanism. The propositus is a 9 month old Caucasian boy from Dothan AL who was found to have a low O2 saturation prior to an ENT procedure. He was referred to cardiology at Children’s Health System, Birmingham, AL to rule out a congenital heart disease. A low O2 saturation (85–86%) was confirmed. Cardiac catheterization excluded the structural abnormality of the heart. Cooximetry showed a normal PaO2 but confirmed a low O2 saturation. Methemoglobin level was 20%, while methemoglobin reductase activity was in the low–normal range but when repeated was found to be normal. His growth and development have been normal. On alkaline electrophoresis an abnormal hemoglobin band was observed. The patient’s blood was sent to the Hemoglobinopathy Laboratory of the Sickle Cell Center at MCG, Augusta, GA for definite identification of the variant. CBC revealed a RBC of 4.3 M/mm3, HGB 13.6 g/dL, HCT 40.8 %, MCV 95.2 fl, MCH 31.8 pg MCHC 33.4 g/dL, Retics 4.4 %. Isoelectrofocusing (IEF) on agarose showed the presence of an abnormal Hb with approximately the same isoelectric point (pI) as Hb F. Quantitation of Hb components by Cation Exchange HPLC revealed 62.7% Hb A, 27.9% Hb X, 3.0% Hb A2, and 6.4% Hb F. By globin chain analyses with reversed phase HPLC, βχ was detected as 37.6% of the total beta chains. Isopropanol stability test gave strongly positive results. P50 was found to be 24.8 mm Hg in the patient and 26.4 in the control (slightly increased oxygen affinity). Peptide analysis was done using mass spectrometry (Alphalyse, Palo Alto, CA) where tryptic digests of purified Hb X (95.0% enriched) and normal control (97.0% Hb A) were analyzed and compared. Peptide 19–30 of helix-B fragment revealed 1314 Da mass in control, whereas peptide 19–29 (with –Gly) of helix-B fragment of Hb X gave 1257 Da mass, confirming the deletion of a Gly residue. The corresponding deletion of three nucleotides (-GTG) in the genomic DNA (codons 25–26: GTGGAG→GAG ) was demonstrated by polymerase chain reaction (PCR) amplification and direct sequencing of β-globin gene and confirmed by cDNA sequencing of β-globin mRNA. No abnormality was detected in the sequences of δ, Gγ, Aγ, α1 and α2 globin genes. The three nucleotide deletion between codons 25 and 26 (-GTG) of the β-globin gene causes a one amino acid (-Gly) deletion in the B helix (B7/B8) of the β-globin chain, however does not alter the amino acid composition of β-globin chain after the deletion point but results in a shorter (145 AA, instead of the normal 146) mutant β-globin chain. As a result close spatial contact of amino acids in tertiary structure of hemoglobin is altered completely. Most importantly, distal histidine at residue 63 of E7 helix now becomes Gly leading to methemoglobin formation. A similar variant was previously reported in a Japanese baby, Hb Higashitochigi (Fujisawa et al, Hemoglobin, 17:467, 1993) where a three nucleotide deletion in codons 24/25 also resulted in the loss of a single Gly residue with a similar outcome. These two cases differ from the known M-hemoglobins all of which result from single amino acid substitution in the E or F-helices thus altering the heme pocket. Hb Dothan and Hb Higashitochigi represent a novel mechanism for M-hemoglobin generation where an in frame deletion alters the tertiary structure of the globin chain with alterations in the structure of E-helix and loss of the distal histidine residue.

scholarly journals Comparison of Genome Sequences of Single-Stranded RNA Viruses Infecting the Bivalve-Killing Dinoflagellate Heterocapsa circularisquama

2005 ◽  
Vol 71 (12) ◽  
pp. 8888-8894 ◽  
Author(s):  
Keizo Nagasaki ◽  
Yoko Shirai ◽  
Yoshitake Takao ◽  
Hiroyuki Mizumoto ◽  
Kensho Nishida ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tertiary Structure ◽  
Rna Virus ◽  
Open Reading Frames ◽  
Host Cells ◽  
Capsid Proteins ◽  
Amino Acid Substitutions ◽  
Virus Surface ◽  
Heterocapsa Circularisquama ◽  
Host Parasite

ABSTRACT Heterocapsa circularisquama RNA virus (HcRNAV) has at least two ecotypes (types UA and CY) that have intraspecies host specificities which are complementary to each other. We determined the complete genomic RNA sequence of two typical HcRNAV strains, HcRNAV34 and HcRNAV109, one of each ecotype. The nucleotide sequences of the viruses were 97.0% similar, and each had two open reading frames (ORFs), ORF-1 coding for a putative polyprotein having protease and RNA-dependent RNA polymerase (RdRp) domains and ORF-2 encoding a single major capsid protein. Phylogenetic analysis of the RdRp amino acid sequence suggested that HcRNAV belongs to a new previously unrecognized virus group. Four regions in ORF-2 had amino acid substitutions when HcRNAV34 was compared to HcRNAV109. We used a reverse transcription-nested PCR system to amplify the corresponding regions and also examined RNAs purified from six other HcRNAV strains with known host ranges. We also looked at natural marine sediment samples. Phylogenetic dendrograms for the amplicons correlated with the intraspecies host specificities of the test virus strains. The cloned sequences found in sediment also exhibited considerable similarities to either the UA-type or CY-type sequence. The tertiary structure of the capsid proteins predicted using computer modeling indicated that many of the amino acid substitutions were located in regions on the outside of the viral capsid proteins. This strongly suggests that the intraspecies host specificity of HcRNAV is determined by nanostructures on the virus surface that may affect binding to suitable host cells. Our study shows that capsid alterations can change the phytoplankton-virus (host-parasite) interactions in marine systems.

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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