[Remantadine-resistant and remantadine-sensitive variants of the influenza virus have different structures of hemagglutinin and matrix protein genes].
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Adamantane↗
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Results for “structural variants”
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Hemoglobin Yukuhashi (Dhofar): E2 (58)beta proline yields arginine: structural and oxygen equilibrium studies of the variant found in two unrelated familes.
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Amino Acids↗
[Structural changes in the myocardium during intermediate variants of chronic ischemic heart disease].
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Adult↗
[Structural analysis of a new slow migration variant of hemoglobin---Hb Duan (alpha 75(EF4)Asp leads to Ala) (author's transl)].
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Amino Acid Sequence↗
Structural determination of a new electrophoreticaly silent variant: hemoglobin Alzette, beta 104(G6)Arg --> Lys.
A new electrophoreticaly neutral hemoglobin variant was found by ion-exchange high-performance liquid chromatography (HPLC). The molecular mass of the beta-chain was shifted down 28 mass units. The modification was found in the beta T-11 peptide that co-elutes with beta T-14 in the tryptic HPLC profile. Collision-induced decomposition of the protonated modified peptide indicated the Arg --> Lys exchange at the C-terminus. This modifies the fragmentation pattern as charge-remote processes induced by the strong basicity of arginine were replaced by charge-induced mechanisms. The exchanged 104Arg is one of the chloride binding sites in the central cavity of Hb.
Amino Acid Sequence↗
Structure and selection of hepatitis B virus variants during the natural course of infection and interferon therapy.
The consequences of hepatitis B virus (HBV) infection range from asymptomatic transient and chronic infections to mild and severe forms of hepatitis up to the development of liver cirrhosis and hepatocellular carcinoma. Immune-mediated destruction of infected liver cells plays a major role in HBV pathogenesis. Escape from immune-recognition by changing the antigenic make-up of HBV or by preventing the expression of some viral proteins leads to the emergence of viral variants. Variants can harbor mutations in the pre-core/core gene (pre C/C) or the preS/S gene, either of which can play a role in immune escape, viral persistence, and pathogenesis. A novel method has been developed to facilitate identification and functional analysis of full-length variant genomes of HBV, with implications for HBV diagnosis and therapy.
Genetic Variation↗
Structure of the human myelin/oligodendrocyte glycoprotein gene and multiple alternative spliced isoforms.
Myelin/oligodendrocyte glycoprotein (MOG), a specific component of the central nervous system localized on the outermost lamellae of mature myelin, is a member of the immunoglobulin superfamily. We report here the organization of the human MOG gene, which spans approximately 17 kb, and the characterization of six MOG mRNA splicing variants. The intron/exon structure of the human MOG gene confirmed the splicing pattern, supporting the hypothesis that mRNA isoforms could arise by alternative splicing of a single gene. In addition to the eight exons coding for the major. MOG isoform, the human MOG gene also contains, in the 3' region, a previously unknown alternatively spliced coding exon, VIA. Alternative utilization of two acceptor splicing sites for exon VIII could produce two different C-termini. The nucleotide sequences presented here may be a useful tool to study further possible involvement of the MOG gene in hereditary neurological disorders.
Alternative Splicing↗
Alternative splicing modulates the frequency-dependent response of CaMKII to Ca(2+) oscillations.
Ca(2+) oscillations are required in various signal trans duction pathways, and contain information both in their amplitude and frequency. Remarkably, the Ca(2+)/calmodulin(CaM)-dependent protein kinase II (CaMKII) can decode such frequencies. A Ca(2+)/CaM-stimulated autophosphorylation leads to Ca(2+)/CaM-independent (autonomous) activity of the kinase that outlasts the initial stimulation. This autonomous activity increases exponentially with the frequency of Ca(2+) oscillations. Here we show that three beta-CaMKII splice variants (beta(M), beta and beta(e)') have very similar specific activity and maximal autonomy. However, their autonomy generated by Ca(2+) oscillations differs significantly. A mechanistic basis was found in alterations of the CaM activation constant and of the initial rate of autophosphorylation. Structurally, the splice variants differ only in a variable 'linker' region between the kinase and association domains. Therefore, we propose that differences in relative positioning of kinase domains within multimeric holoenzymes are responsible for the observed effects. Notably, the beta-CaMKII splice variants are differentially expressed, even among individual hippocampal neurons. Taken together, our results suggest that alternative splicing provides cells with a mechanism to modulate their sensitivity to Ca(2+) oscillations.
Alternative Splicing↗
Poliovirus neutralization epitopes: analysis and localization with neutralizing monoclonal antibodies.
Two hybridomas (H3 and D3) secreting monoclonal neutralizing antibody to intact poliovirus type 1 (Mahoney strain) were established. Each antibody bound to a site qualitatively different from that to which the other antibody bound. The H3 site was located on intact virions and, to a lesser extent, on 80S naturally occurring empty capsids and 14S precursor subunits. The D3 site was found only on virions and empty capsids. Neither site was expressed on 80S heat-treated virions. The antibodies did not react with free denatured or undenatured viral structural proteins. Viral variants which were no longer capable of being neutralized by either one or the other antibody were obtained. Such variants arose during normal cell culture passage of wild-type virus and were present in the progeny viral population on the order of 10(-4) variant per wild-type virus PFU. Toluene-2,4-diisocyanate, a heterobifunctional covalent cross-linking reagent, was used to irreversibly bind the F(ab) fragments of the two antibodies to their respective binding sites. In this way, VP1 was identified as the structural protein containing both sites.
Animals↗
Constraints among molecular and systemic properties: implications for physiological genetics.
Physiological genetics attempts to relate the molecular genetic properties of an organism--the genotype--to its integrated or physiological behavior--the phenotype. There has been relatively little progress in this field when compared to the neighboring fields of molecular and population genetics. This is due in part to the large number of highly non-linear interactions that characterize such systems. Biochemical Systems Theory is one approach that shows promise in dealing with the large number of non-linear interactions in a systematically structured manner. A variant of this approach has stressed the use of specific mathematical constraints, called summation and connectivity relationships, among molecular and systemic properties. In particular, the summation relationship has been used to argue that the predominance of recessive mutations is the inevitable consequence of the kinetic structure of enzyme networks and need not be attributed to natural selection. In order to put in broader perspective the implications of such constraints for physiological genetics, we have presented in this paper the outlines of the larger theory and the set of generalized steady state constraints that follow from first principles within this theory. The results show that the summation relationship suffers from a number of fundamental limitations that make it invalid for analyzing realistic biological systems. It also is shown that the more general constraint relationships, while valid, provide nothing new that cannot be obtained directly from the explicit solutions that are available within the larger theory. Thus, one can conclude that approaches based directly on the underlying equations of the system are superior to those based upon constraint relationships as a foundation for the development of physiological genetics.
Genotype↗
Single-site mutations in a hyperthermophilic variant of the B1 domain of protein G result in self-assembled oligomers.
We have characterized two homologous, single-point core mutants of a 57-residue, hyperthermophilic variant of the B1 domain of protein G (HTB1). These single-point mutations in HTB1 replace a Phe residue in the hydrophobic core with either a Glu or Asp residue. Both of these homologous core-variant mutants undergo significant structural rearrangement from the native, monomeric fold and exist as stable soluble oligomeric species of 5 and 30 nm in diameter. Gel-filtration, dynamic light scattering, circular dichroism spectroscopy, fluorescence spectroscopy, along with Congo Red and Thioflavin T binding clearly demonstrated that these core-variants undergo significant structural rearrangement from the native, monomeric ubiquitin fold. The two oligomeric species did not equilibrate over extended periods of time and displayed distinct secondary structures. The larger of the two species was found to possess structural features that are reminiscent of an emerging class of protein assemblies prone to beta-sheet-mediated aggregation. These results are significant as there are very few examples of extensive conformational or oligomerization switching brought about by single-point mutations in a stable protein-fold.
Amino Acid Sequence↗
[MRI as a diagnostic technique in examination of the shoulder joint].
The paper presents the results of examination of 95 patients with shoulder joint abnormality to define the capacities of MR imaging in the evaluation of the anatomic structures of this joint. It details the MR anatomic features of the shoulder joint. Some conditions should be adhered to while performing MRI of the joint, namely: to obtain high-quality images by correctly choosing pulse sequences and scanning planes and to know the anatomic variants of the structure of the shoulder joint.
Humans↗
Readthrough acetylcholinesterase expression remains minor after stress or exposure to inhibitors.
The gene of mammalian acetylcholinesterase (AChE) generates multiple molecular forms, by alternative splicing of its transcripts and association of the tailed variant (AChET) with structural proteins. In the mammalian brain, the major AChE species consists of AChET tetramers anchored to the cell membrane of neurons by the PRiMA protein (Perrier et al., 2002). Stress and anticholinesterase inhibitors have been reported to induce rapid and long-lasting expression of the readthrough variant (AChER) in the mouse brain (Kaufer et al., 1998). In the readthrough transcript, there is no splicing after the last exon encoding the catalytic domain, so that the entire alternatively spliced 3' region is maintained. It encodes a C-terminal peptide with no specific interaction properties: COS cells transfected with AChER produce a soluble, nonamphiphilic monomeric form. We quantified AChER and total AChE expression in the mouse brain after an immobilization stress and after heat shock in neuroblastoma cells, and compared the observed effects with those induced by irreversible AChE inhibition (Perrier et al., 2005).
Acetylcholinesterase↗
Deep learning-based assessment of missense variants in the COG4 gene presented with bilateral congenital cataract.
OBJECTIVE: We compared the protein structure and pathogenicity of clinically relevant variants of the COG4 gene with AlphaFold2 (AF2), Alpha Missense (AM), and ThermoMPNN for the first time. METHODS AND ANALYSIS: The sequences of clinically relevant Cog4 missense variants (one novel identified p.Y714F and three pre-existing p.G512R, p.R729W and p.L769R from Uniprot Q9H9E3) were imported into AF2 for protein structural prediction, and the pathogenicity was estimated using AM and ThermoMPNN. Different pathogenicity metrics were aggregated with principal component analysis (PCA) and further analysed at three levels (amino acid position, substitution and post-translation) based on all possible Cog4 missense variants (n=14 915). RESULTS: Localised protein structural impact including change of conformation and amino acid polarity, breakage of hydrogen bond and salt-bridge, and formation of alpha-helix were identified among clinically relevant Cog4 variants. The global structural comparison with multidimensional scaling demonstrated variants with similar protein structures (AF2) tended to exhibit similar clinical and biological phenotypes. The Cog4 p.Y714F variant exhibited greater protein structural similarity to mutated Cog4 found in Saul‒Wilson syndrome (p.G512R) and shared similar clinical phenotype (congenital cataract and psychomotor retardation). PCA of included pathogenic metrics demonstrated p.Y714F occurred at a critical position in Cog4 amino acid sequence with disrupted post-translational phosphorylation. CONCLUSION: Deep learning algorithms, including AF2, AM and ThermoMPNN, can be useful for evaluating variant of uncertain significance (VUS) by structural and pathogenicity prediction. Despite classified as VUS (American College of Medical Genetics and Genomics criteria: PM1, PP4), the pathogenicity in this Cog4 variant cannot be ruled out and warrants further investigation.
Mutation, Missense↗
The importance of the strictly conserved, C-terminal glycine residue in phosphoenolpyruvate carboxylase for overall catalysis: mutagenesis and truncation of GLY-961 in the sorghum C4 leaf isoform.
Phosphoenolpyruvate carboxylase (PEPC) is a "multifaceted," allosteric enzyme involved in C4 acid metabolism in green plants/microalgae and prokaryotes. Before the elucidation of the three-dimensional structures of maize C4 leaf and Escherichia coli PEPC, our truncation analysis of the sorghum C4 homologue revealed important roles for the enzyme's C-terminal alpha-helix and its appended QNTG961 tetrapeptide in polypeptide stability and overall catalysis, respectively. Collectively, these functional and structural observations implicate the importance of the PEPC C-terminal tetrapeptide for both catalysis and negative allosteric regulation. We have now more finely dissected this element of PEPC structure-function by modification of the absolutely conserved C-terminal glycine of the sorghum C4 isoform by site-specific mutagenesis (G961(A/V/D)) and truncation (DeltaC1/C4). Although the C4 polypeptide failed to accumulate in a PEPC- strain (XH11) of E. coli transformed with the Asp mutant, the other variants were produced at wild-type levels. Although neither of these four mutants displayed an apparent destabilization of the purified PEPC homotetramer, all were compromised catalytically in vivo and in vitro. Functional complementation of XH11 cells under selective growth conditions was restricted progressively by the Ala, DeltaC1 and Val, and DeltaC4 modifications. Likewise, steady-state kinetic analysis of the purified mutant enzymes revealed corresponding negative trends in kcat and kcat/K0.5 (phosphoenolpyruvate) but not in K0.5 or the Hill coefficient. Homology modeling of these sorghum C-terminal variants against the structure of the closely related maize C4 isoform predicted perturbations in active-site molecular cavities and/or ion-pairing with essential, invariant Arg-638. These collective observations reveal that even a modest, neutral alteration of the PEPC C-terminal hydrogen atom side chain is detrimental to enzyme function.
Allosteric Site↗
Structure of the mouse gonadotropin-releasing hormone receptor gene: variant transcripts generated by alternative processing.
The mouse gonadotropin-releasing hormone receptor (GnRHR) is unique among G-protein-coupled receptors in its lack of a putative intracellular carboxy-terminal domain. A gonadotrope cell line cDNA library was screened in a search for alternative forms of the receptor transcript and 42 clones were obtained, representing a number of variant cDNAs. To determine the origin of these transcripts, the structure of the mouse gene was mapped from 11 distinct genomic clones. The gene contains three exons, spanning more than 22 kb. Exons 1, 2, and 3 encode, respectively, nucleotides +1 to +522, +523 to +739, and +740 to +981 of the open reading frame of the cDNA for the functional mouse GnRHR. Southern blot analysis with genomic DNA is consistent with the presence of a single gene. By comparison with the genomic sequence, the origins of the variant cDNAs isolated can be clarified. All the cDNAs contain the first exon and the majority (71%) encode the functional 327-amino-acid receptor previously reported. One group of clones (14%), which contains exons 1 and 2, continues 700 bp past the exon 2 splice donor of the wild-type receptor. These clones terminate after a polyadenylation signal and have an open reading frame encoding a protein of only 261 amino acids. In a different group of transcripts (5%), exon 2 is absent, resulting in a shift in the reading frame and encoding a protein of 177 amino acids. These data support alternative processing of the mouse GnRHR gene.
Alternative Splicing↗
[Fatty acid synthases--strategic functions of multienzymes].
Several decades of biochemical research have led to our present detailed knowledge on cellular metabolism, is wealth of individual reactions, enzymes, and pathways, and their organization, interplay, and regulation. Although most metabolic reactions are simultaneous and occur in the same cell, they may also act independently of one other and without causing disturbing interferences. This demonstrates that the cellular interior is organized structurally and functionally and is not simply a "bag of enzymes." This organization ranges from distinct and functionally specialized organelles down to subtle or even hypothetical structures at the molecular level. The lowest level of structurally stable, supramolecular catalytic entities in the cell thus for known is that of the multienzyme complexes. Among the limited number of known multi-enzymes, fatty acid synthase is certainly one of the most complex and also best studied. Various structural and functional variants of this multienzyme system are known. These may be discussed in terms of specific requirements of the respective organisms.
Acyl Coenzyme A↗
Structural and spectroscopic studies of azide complexes of horse heart myoglobin and the His-64-->Thr variant.
The high-resolution X-ray crystallographic structures of horse heart azidometmyoglobin complexes of the wild-type protein and the His-64-->Thr variant have been determined to 2.0 and 1.8 A respectively. Azide binds to wild-type metmyoglobin in a bent configuration with an Fe-N-1-N-3 angle of 119 degrees and is oriented into the distal crevice in the direction of Ile-107. The proximity of the His-64 NE2 atom to the N-1 atom of the bound azide indicates stabilization of the ligand by the His-64 side chain through hydrogen bonding. In addition, structural characterization of wild-type horse heart azidometmyoglobin establishes that the only structural change induced by ligand binding is a small movement of the Leu-29 side chain away from the azide ligand. EPR and Fourier transform infrared spectroscopy were used to characterize the myoglobin azide complexes further. EPR spectroscopy revealed that, in contrast with wild-type azidometmyoglobin, two slightly different low-spin species are formed by azide bound to the His-64-->Thr variant both in solution and in a polycrystalline sample. One of these low-spin species has a greater relative intensity, with g values very similar to those of the azide complex of the wild-type protein. These EPR results together with structural information on this variant indicate the presence of two distinct conformations of bound azide, with one form predominating. The major conformation is comparable to that formed by wild-type myoglobin in which azide is oriented into the distal crevice. In the minor conformation the azide is oriented towards the exterior of the protein.
Animals↗