Aldolase variants: structure and physiological significance.
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Animals↗
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HLA class II variants: structural studies and disease associations.
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Arthritis, Juvenile↗
Gamma structural variants differentially regulate Na,K-ATPase properties.
Renal Na,K-ATPase is tightly bound to a small regulatory protein, the gamma subunit (FXYD2). In rat, it occurs in two splice variants with different N-termini. Immunolocalization on kidney sections revealed distinct distribution of the gamma splice variants along the rat nephron. Where coexpressed, they coimmunoprecipitated with each other along with the alpha subunit, suggesting assembly in oligomeric complexes. Functional consequences of association with gamma were monitored in stably transfected NRK-52E cells. The outcome was that splice variants can differentially modulate the major intrinsic properties of the Na,K-ATPase under normal and stress-related conditions. The data imply an adaptive physiological mechanism of regulation of renal Na,K-ATPase through modulation of pump properties, gene expression, or both.
Animals↗
Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3).
The constitutive androstane receptor (CAR) mediates the hepatic induction of various xenobiotic metabolizing enzymes and transporters after specific chemical exposures. Recent reports have established the existence of several human CAR mRNA splice variants, including a prominently expressed form termed CAR3, a receptor that possesses a 5 amino acid insertion within its ligand binding domain. In this study, we demonstrate that, in contrast to the constitutively active reference form of the receptor, CAR3 is ligand-activated, transactivating an optimized DR-4 x 3 reporter in response to the human CAR ligand 6-(4-chlorophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde O-(3, 4-dichlorobenzyl)oxime (CITCO). The transactivation response requires the DNA binding domain and AF-2 motif of CAR3 and is markedly enhanced by retinoid X receptor-alpha (RXR) cotransfection. The stimulatory effects of RXR involve a unique mechanism, because they were completely dependent on the RXR AF-2 function but independent of both the RXR A/B domain and its C domain/heterodimerization region. Mammalian two-hybrid results demonstrated that RXR enhanced CITCO-dependent interaction of CAR3 with the receptor interaction domain of SRC-1, indicating that RXR augments CAR3 activity by facilitating coactivator recruitment. It is noteworthy that clotrimazole also functions as a ligand activator of CAR3, in contrast to the inverse agonist activity exhibited by this agent on the reference form of the receptor. Furthermore, results of transfection assays reveal that CAR3 is capable of transactivating the natural CYP2B6 and CYP3A4 gene enhancers, exhibiting both ligand- and RXR-dependence. These results demonstrate that CAR3, unlike CAR1, is a ligand-activated receptor and that CAR3 may regulate gene expression in vivo in a manner distinct from the reference form of the receptor.
Animals↗
Rapid progression to AIDS in HIV+ individuals with a structural variant of the chemokine receptor CX3CR1.
Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and a coreceptor. Which of 15 known coreceptors are important in vivo is poorly defined but may be inferred from disease-modifying mutations, as for CCR5. Here two single nucleotide polymorphisms are described in Caucasians in CX3CR1, an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the chemokine fractalkine. HIV-infected patients homozygous for CX3CR1-I249 M280, a variant haplotype affecting two amino acids (isoleucine-249 and methionine-280), progressed to AIDS more rapidly than those with other haplotypes. Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, CX3CR1-I249 M280 is a recessive genetic risk factor in HIV/AIDS.
Acquired Immunodeficiency Syndrome↗
Immunization of cattle with the MSP-1 surface protein complex induces protection against a structurally variant Anaplasma marginale isolate.
The Anaplasma marginale surface protein complex MSP-1 of the Florida isolate is composed of a 105-kilodalton (kDa) polypeptide, which bears a neutralization-sensitive epitope, and a 100-kDa polypeptide. Antigenically similar polypeptides in the Okanogan, Wash. (Washington-O), isolate MSP-1 are 86 and 100 kDa, respectively. Immunization of cattle with Florida isolate MSP-1 induced antibody titers to both MSP-1 polypeptides and protected cattle against homologous and heterologous challenge.
Anaplasma↗
Structurally variant classes of pilus appendage fibers coexpressed from Burkholderia (Pseudomonas) cepacia.
One or more of five morphologically distinct classes of appendage pili were determined to be peritrichously expressed by Burkholderia (formerly Pseudomonas) cepacia isolated from disparate sources. B. cepacia-encoded cblA pilin gene hybridization-based analysis revealed that one associated class, cable (Cbl) adhesin type IIB. cepacia pili, correlates with epidemically transmitted strains from a single cystic fibrosis (CF) center. When only phenotypic assays were available, correlations between the source and the pilus type were nonetheless observed: filamentous (Fil) type IIIB. cepacia pili correlated with CF-associated nonepidemic isolates, spine (Spn) type IVB. cepacia pili correlated with clinical (non-CF) isolates, and spike (Spk) type VB. cepacia pili correlated with environmental isolates. Further, Cbl, Fil, or Spk pili typically appear as an internal framework for constitutively coexpressed, peritrichously arranged dense mats of fine, curly mesh (Msh) type IB. cepacia pili. Constitutive coexpression of dense mats of Msh type IB. cepacia pili in association with a labyrinth of either Cbl, Fil, or Spk pili suggests possible cooperative pilus interactions mediating adhesion-based colonization in the differing environments from which the strains were isolated. Despite such correlations, phylogenetic analyses indicate that with the exception of the epidemically transmitted clusters of isolates, the remaining B. cepacia strains from the other three sources exhibited an equal degree of genetic relatedness independent of origin. As previously found for Escherichia coli, this discrepancy could be accounted for by selection-driven, in vivo horizontal transfer events between distantly related members of the species B. cepacia, leading to the genetic acquisition of environmentally appropriate adhesion-based colonization pilus operons.
Bacterial Outer Membrane Proteins↗
Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy.
Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.
HIV Protease↗
Strain-dependent structural variants of herpes simplex virus type 1 ICP34.5 determine viral plaque size, efficiency of glycoprotein processing, and viral release and neuroinvasive disease potential.
The ability of certain strains of herpes simplex virus type 1 (HSV-1) to cause encephalitis or neuroinvasive disease in the mouse upon peripheral infection is dependent on a combination of activities of specific forms of viral proteins. The importance of specific variants of ICP34.5 to neuroinvasive disease potential and its correlation with small-plaque production, inefficient glycoprotein processing, and virus release were suggested by comparison of ICP34.5 from the SP7 virus, originally obtained from the brain of a neonate with disseminated disease, and the tissue culture-passaged progeny of SP7 (SLP5 and SLP10) and the KOS321 virus. SLP5, SLP10, and KOS321 are attenuated and exhibit a large-plaque phenotype, including efficient glycoprotein processing and viral release. We show that expression of the KOS321 ICP34.5 protein in cells infected with SP7 or ICP34.5 deletion mutants promotes large plaque formation and efficient viral glycoprotein processing, while expression of the SP7 ICP34.5 protein decreases efficiency of viral glycoprotein processing. In addition, a recombinant virus, 4hS1, with the SP7 ICP34.5 gene replacing the KOS321-like ICP34.5 gene in the SLP10a background, rescues the small-plaque phenotype and neuroinvasive disease. The major difference in the ICP34.5 gene product is the number of Pro-Ala-Thr repeats in the middle region of the protein, with 18 for SP7 and 3 for KOS321. Strain-dependent differences in the ICP34.5 protein can therefore alter the tissue culture behavior and the virulence of HSV-1.
Animals↗
Molecular population genetics of structural variants of esterase 6 in Drosophila melanogaster.
Several lines of evidence indicate that natural selection operates between the major EST6-F and EST6-S allozymes of Drosophila melanogaster. In particular, consistent latitudinal clines and seasonal variation in their relative frequencies strongly suggest that they are not selectively equivalent in field populations. Several laboratory studies have found frequency-dependent fitness differences among the Est6-F and Est6-S genotypes. Moreover, the purified EST6-F and EST6-S allozymes differ in biochemical properties and the physiology of the enzyme, as a major component of the seminal fluid, suggests that these differences could affect reproductive aspects of fitness. However, molecular analyses reveal high levels of variation in the EST6 protein both within and between the EST6-F and EST6-S allozymes. Limited thermostability and more sensitive electrophoretic analyses reveal at least 17 variants of the two allozymes and sequence comparisons among 13 isolates of the Est6 gene reveal 16 nucleotide polymorphisms that would lead to amino acid differences. Two closely linked amino acid differences are strongly associated with the major difference between EST6-F and EST6-S; either or both of these are likely to cause the observed biochemical differences between EST6-F and EST6-S and may be the primary targets for the selection between these allozymes. The functional and adaptive significance of the other amino acid polymorphisms is unclear, although the data suggest that the EST6-8 haplotype within EST6-S has both arisen and proliferated relatively recently.
Alleles↗
Structural variants of human growth hormone: biochemical, genetic, and clinical aspects.
Human growth hormone (hGH) is a mixture of peptides in which the major physiologic component is a single chain polypeptide of 191 residues with a molecular weight of 22,000 ("22K" form). The minor components differ from the 22K form in terms of mass (e.g. the 20K form, a single-chain peptide synthesized by deletion of residues 32-46 of the 22K isomer, and the 45K variant formed by aggregation of the 22K molecule), or of charge (e.g. the more acidic two-chain forms alpha 2 and alpha 3 which are generated by proteolytic deletion of residues 135-140 and 135-146 from the 22K variant). The minor components also differ from the 22K molecule in (a) their metabolic effects; (b) their capacity to bind to antiserum raised against the 22K form in a radioimmunoassay (RIA); and (c) their ability to bind to membrane receptors for the 22K hGH in a radioreceptor assay (RRA). Two genes, N and V, involved in the biosynthesis of hGH, are located on human chromosome 17. Heritable alterations of the N gene may cause deficiency of immunoreactive hGH and growth failure. A pathologic variant of hGH has also been identified which is indistinguishable from the 22K form on RIA, but which has low reactivity on hGH-RRA and low somatomedogenic activity. Several mechanisms to account for this bioinactive variant are discussed.
Child↗
Structural variants of a human 5-HT1a receptor intracellular loop 3 peptide.
To better understand cytoplasmic loop 3/G protein coupling, variations in a bioactive synthetic peptide probe (P1) were constructed according to the published sequences of the human 5HT1a receptor. These probes were tested in a model system of human 5HT1a receptor stably expressed in Chinese hamster ovary cells. In agonist inhibition studies, peptides with amino acid substitutions of residues 6-9 from the amino terminus of loop 3 were less active than P1. Truncated peptide P4, conserving the residue 6-9 region, was also less active than P1. Truncates P5 and P6, deleting the residue 6-9 region, were inactive. When cAMP levels were measured, both substituted peptides were more active than P1 in this negatively coupled system. In contrast, the truncated peptides were without activity in the cAMP assays. Thus, P1 and its derivatives (P2-P6) constitute a small group of peptides with differential uncoupling (agonist inhibition) and signal transduction (cAMP) activities in this G-protein-linked system. It is proposed that these peptides will be useful in future studies detailing the molecular determinants at the receptor/G protein interface.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Identification of a new structural variant of human apolipoprotein E, E2(Lys146 leads to Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype.
A type III hyperlipoproteinemic subject having the apolipoprotein E (apo E) phenotype E3/2 was identified. From isoelectric focusing experiments in conjunction with cysteamine treatment (a method that measures cysteine content in apo E), the E2 isoform of this subject was determined to have only one cysteine residue, in contrast to all previously studied E2 apoproteins, which had two cysteines. This single cysteine was shown to be at residue 112, the same site at which it occurs in apo E3. From amino acid and sequence analyses, it was determined that this apo E2 differed from apo E3 by the occurrence of glutamine rather than lysine at residue 146. When phospholipid X protein recombinants of the subject's isolated E3 and E2 isoforms were tested for their ability to bind to the human fibroblast apo-B,E receptor, it was found that the E3 bound normally (compared with an apo E3 control) but that the E2 had defective binding (approximately 40% of normal). Although they contained E3 as well as E2, the beta-very low density lipoproteins (beta-VLDL) from this subject were very similar in character to the beta-VLDL from an E2/2 type III hyperlipoproteinemic subject; similar subfractions could be obtained from each subject and were shown to have a similar ability to stimulate cholesteryl ester accumulation in mouse peritoneal macrophages. The new apo E2 variant has also been detected in a second type III hyperlipoproteinemic subject.
Aged↗
New results of hemoglobin variant structure determinations by fast atom bombardment mass spectrometry.
Fast atom bombardment mass spectrometry has already been used for the identification of mutations in abnormal human hemoglobin chains. This paper presents new results obtained with this technique. The methodology used here is compared with more conventional biochemical techniques and automated microsequencing. In every case, a well-chosen combination of peptide-high performance liquid chromatography, mass spectrometry, amino acid analysis, and sequence analysis led rapidly to the identification of the mutant. The high sensitivity of these techniques holds great promise for the analysis of molecular abnormalities in various genetic disorders presently detectable only by the application of a molecular biological approach.
Adult↗
A natural structural variant of the mouse TCR beta-chain displays intrinsic receptor function and antigen specificity.
The Cbeta0 alternate cassette exon is located between the Jbeta1 and Cbeta1 genes in the mouse TCR beta-locus. In T cells with a VDJbeta1 rearrangement, the Cbeta0 exon may be included in TCRbeta transcripts (herein called TCRbeta-Cbeta0 transcripts), potentially inserting an additional 24 aa between the V and C domains of the TCR beta-chain. These TCRbeta splice isoforms may be differentially regulated after Ag activation, because we detected TCRbeta-Cbeta0 transcripts in a high proportion (>60%) of immature and mature T cells having VDJbeta1 rearrangements but found a substantially reduced frequency (<35%) of TCRbeta-Cbeta0 expression among CD8 T cells selected by Ag in vivo. To study the potential activity of the TCRbeta-Cbeta0 splice variant, we cloned full-length TCR cDNAs by single-cell RT-PCR into retroviral expression vectors. We found that the TCRbeta-Cbeta0 splice isoform can function during an early stage of T cell development normally dependent on TCR beta-chain expression. We also demonstrate that T hybridoma-derived cells expressing a TCRbeta-Cbeta0 isoform together with the clonally associated TCR alpha-chain recognize the same cognate peptide-MHC ligand as the corresponding normal alphabetaTCR. This maintenance of receptor function and specificity upon insertion of the Cbeta0 peptide cassette signifies a remarkable adaptability for the TCR beta-chain, and our findings open the possibility that this splice isoform may function in vivo.
Animals↗
[Structural variants of intracellular flagella and centrioles in nevus cells].
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Cell Membrane↗
[Embolization of the hepatic artery in cases of atypical anatomical structural variants in patients with malignant liver tumors].
Therapeutic embolization of the hepatic artery was performed in 60 patients with nonresectable malignant liver tumors. Atypical topographical anatomical variants of the arterial system of the liver were revealed in 10 of them (16.7%). In 8 patients two hepatic vessels, one coming out of the celiac artery, the other--out of the upper mesenterial or left gastric artery supplied a tumor with blood. In three of them one vessel was embolized, in five patients both arteries were embolized. The blocking of the entire blood flow of a tumor brought about a positive clinical effect in all the patients. Embolization of one blood-supplying artery alone led to no improvement. A conclusion was made of a necessity to achieve arterial devascularization of the entire tumor tissue area during intravascular therapy.
Embolization, Therapeutic↗
A spontaneous mutation produced a novel elongated beta-globin chain structural variant (Hb Agnana) with a thalassemia-like phenotype.
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Adult↗