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At least 19 recordsLinked to original sources
PubMed1990

Characterization of the repertoire of hypervariable regions in the Protein II (opa) gene family of Neisseria gonorrhoeae.

P.II outer membrane proteins of Neisseria gonorrhoeae are encoded by a family of closely related genes. Although the genes are highly conserved, major differences in sequence among them occur in two short regions, designated hypervariable regions 1 (HV1) and 2 (HV2). In this study, we determined the number and DNA sequence of the hypervariable regions in the P.II genes of strains FA1090. The FA1090 chromosome contained at least eleven P.II loci, having six different versions each of HV1 and HV2 among them. Southern blotting with HV-specific oligonucleotides showed that each version was present in one to three copies, and that there were nine unique combinations of HV1 and HV2 in the P.II genes. Although each of the versions of HV1 or HV2 had a unique DNA sequence, there were some similarities among them, particularly when certain ones were compared. Restriction fragments containing only the HV regions were cloned into an expression vector to demonstrate that the epitopes recognized by a set of monoclonal antibodies specific for different FA1090 P.II proteins were completely encoded by either HV1 or HV2.

Amino Acid Sequence↗
PubMed1991

Prevalence of gene sequences coding for hypervariable regions of Opa (protein II) in Neisseria gonorrhoeae.

Opas (protein IIs) are a family of surface-exposed proteins of Neisseria gonorrhoeae. Each strain of N. gonorrhoeae has multiple (10-11) genes encoding for Opas. Identifiable elements in opa genes include the coding repeat within the signal sequence, conserve 5' and 3' regions, and hypervariable regions (HV1 and HV2) located within the structural gene. N. gonorrhoeae strains appear to have many biological properties in common that are either HV-region-mediated or associated with the presence of specific HV regions, suggesting that HV regions could be found in many clinical isolates. Oligonucleotides from three source strains representing three conserved regions of opa, 12 HV1 regions, and 14 HV2 regions were used by dot blot analysis to probe 120 clinical isolates of N. gonorrhoeae. The probe for the coding repeat hybridized to all 120 strains, the 3' conserved-region probe reacted with 98% of the strains, and the 5' conserved-region probe with 90% of the strains. Nine HV1 probes hybridized to 3.3-39.2% of the strains, and 13 of the HV2 probes hybridized to 1.7-25% of the isolates. Analysis of the number of probes that hybridized to each of the isolates showed that 19% did not hybridize with any of the HV1 probes and 25% did not hybridize with any of the HV2 probes. Approximately three-quarters of the isolates hybridized with one, two or three of the HV1 probes or one, two or three of the HV2 probes; 89% of the isolates hybridized to least one HV1 or one HV2 probe. The data indicate that some genes encoding HV regions of N. gonorrhoeae Opa proteins are widely distributed in nature.

Bacterial Outer Membrane Proteins↗
PubMed1985

Production of heterologous antibodies specific for murine B-cell leukemia (BCL1) immunoglobulin by immunization with synthetic peptides homologous to heavy chain hypervariable regions.

Three peptides homologous to each heavy chain hypervariable region expressed by murine B-cell leukemia, BCL1, were synthesized in vitro by solid phase peptide synthesis. All three synthetic peptides elicited responses in rabbits which were immunized with synthetic peptide or synthetic peptide conjugated to the carrier keyhole limpet hemocyanin. Six individual rabbits were immunized, five of which responded by producing antisera which react specifically in radioimmunoassay with the synthetic peptide used as immunogen. One antiserum has specificity for the peptide homologous to the first hypervariable region, three antisera have specificity for the peptide homologous to the second hypervariable region, and one has specificity for the peptide homologous to the third hypervariable region. The five antisera with high titers of antibody recognizing synthetic peptide also specifically recognize native immunoglobulin M secreted by BCL1 tumor cells as demonstrated by immunoprecipitation followed by sodium dodecyl sulfate: polyacrylamide gel electrophoresis and autoradiography. These five antisera do not show reactivity with immunoglobulin secreted by spleen cells from normal BALB/cAn mice or by B-cells from unrelated tumors and cell lines. However, as determined by absorption experiments, the majority of antibodies in each antiserum are directed against the respective synthetic peptide, and only a small portion are reactive with native immunoglobulin M. Nonetheless, these results indicate use of synthetic peptides as a potential alternative source of immunogen for production of antitumor antibody.

Amino Acid Sequence↗
PubMed1991

Design of bioactive peptides based on antibody hypervariable region structures. Development of conformationally constrained and dimeric peptides with enhanced affinity.

The variable regions of antibody molecules bind antigens with high affinity and specificity. This binding is imparted largely by the hypervariable portions of the variable region. Hypervariable regions typically fold into reverse turn or loop structures. Peptides derived from antibody hypervariable region sequences can bind antigens with similar specificity, albeit with markedly lower affinity. In this study, cyclic and dimeric peptide analogs of an anti-idiotypic/antireceptor antibody hypervariable region were developed. This antibody (87.92.6) binds to reovirus type 3 receptors on cells as well as to a neutralizing anti-reovirus type 3 monoclonal antibody (9B.G5). The cyclic peptides were utilized to probe the optimal conformation for binding to both the receptor and 9B.G5. By dimerizing or constraining the conformation of these peptides, higher affinity binding was produced. By utilizing several different cyclic peptides, the optimal conformation for binding was established. The conformationally optimized cyclic peptide possessed greater than 40-fold higher affinity for the receptor and the idiotype than the linear analog. This study suggests that conformationally constrained and dimeric peptides derived from antibody hypervariable loop sequences can bind antigens (including receptors) with reasonable affinity. hypervariable loop sequences can bind antigens (including

Amino Acid Sequence↗
PubMed1974

Variable region sequences of five human immunoglobulin heavy chains of the VH3 subgroup: definitive identification of four heavy chain hypervariable regions.

The variable regions of five human immunoglobulin heavy chains of the V(H)III subgroup have been totally sequenced. Three of the heavy chains belonged to the IgG class and two to the IgA class. Examination of these sequences, and comparison with additional published heavy chain sequences, showed that a total of four hypervariable regions is characteristic of human heavy chain variable regions. The relatively conserved character of large segments of the heavy chain variable region was very evident in these studies. The conserved segments, which are those sections located outside the hypervariable regions, comprise approximately 65% of the total heavy chain variable region. The following general structural pattern for antibody molecules emerges from this and related studies: an overall combining region superstructure is provided by the more conserved segments while the refinements of the active site specificity are a function of hypervariable regions.

Amino Acid Sequence↗
PubMed1987

Canonical structures for the hypervariable regions of immunoglobulins.

We have analysed the atomic structures of Fab and VL fragments of immunoglobulins to determine the relationship between their amino acid sequences and the three-dimensional structures of their antigen binding sites. We identify the relatively few residues that, through their packing, hydrogen bonding or the ability to assume unusual phi, psi or omega conformations, are primarily responsible for the main-chain conformations of the hypervariable regions. These residues are found to occur at sites within the hypervariable regions and in the conserved beta-sheet framework. Examination of the sequences of immunoglobulins of unknown structure shows that many have hypervariable regions that are similar in size to one of the known structures and contain identical residues at the sites responsible for the observed conformation. This implies that these hypervariable regions have conformations close to those in the known structures. For five of the hypervariable regions, the repertoire of conformations appears to be limited to a relatively small number of discrete structural classes. We call the commonly occurring main-chain conformations of the hypervariable regions "canonical structures". The accuracy of the analysis is being tested and refined by the prediction of immunoglobulin structures prior to their experimental determination.

Amino Acid Sequence↗
PubMed1991

An additional hypervariable region encoded by V gene segments occurs in Tcr V beta at a location compatible with its involvement in Tcr active site--a general model for alloreactivity.

The number of V alpha and V beta sequences of T cell receptors now available allows a meaningful analysis of their variability profiles. Variability plots were derived using a modified form of Wu and Kabat's algorithm: variability is not computed as a proportion of the number of different residues occurring at a position, but rather proportionally to the physicochemical differences between the different residues. Results show that the classical hypervariable regions occurring in immunoglobulins also occur in T cell receptors at equivalent positions. Contrary to immunoglobulins the framework of Tcr V regions displays many relatively variable regions and positions. This phenomenon can be connected with the genetic organization of V genes of T cell receptors which seem to avoid any framework homogenization and the resulting gene conversion. More importantly an additional hypervariable region was detected in V beta but not in V alpha. This fourth hypervariable region is located between the second and the D hypervariable CDR. The predicted three-dimensional location of this additional hypervariable region is compatible with a possible role in antigen recognition and therefore also in positive and/or negative selection. Furthermore our data suggest that this fourth hypervariable region is involved in the recognition of superantigens like bacterial enterotoxins. Indeed this additional hypervariable region is not detected when variability is derived using an alignment of the V beta subgroups stimulated by one toxin of S. aureus. Finally we propose a new and simple molecular model to explain alloreactivity as crossreactivity between the universe of shapes (isomers of conformation) of different MHC haplotypes.

Amino Acid Sequence↗
PubMed1990

Analysis of sequence diversity in hypervariable regions of the external glycoprotein of human immunodeficiency virus type 1.

Nucleotide sequences in three hypervariable regions of the human immunodeficiency virus type 1 (HIV-1) env gene were obtained by sequencing provirus present in peripheral blood mononuclear cells of HIV-infected individuals. Single molecules of target sequences were isolated by limiting dilution and amplified in two stages by the polymerase chain reaction, using nested primers. The product was directly sequenced to avoid errors introduced by Taq polymerase during the amplification process. There was extensive variation between sequences from the same individual as well as between sequences from different individuals. Interpatient variability was markedly less in individuals infected from a common source. A high proportion of amino acid substitutions in the hypervariable regions altered the number and positions of potential N-linked glycosylation sites. Sequences in two hypervariable regions frequently contained short (3- to 15-bp) duplications or deletions, and by amplifying peripheral blood mononuclear cell DNA containing 10(2) or 10(3) proviral molecules and analyzing the product by high-resolution electrophoresis, the total number and abundance of distinct length variants within an individual could be estimated, providing a more comprehensive analysis of the variants present than would be obtained by sequencing alone. Sequences from many individuals showed frequent amino acid substitutions at certain key positions for neutralizing-antibody and cytotoxic T-cell recognition in the immunodominant loop. The rates of synonymous and nonsynonymous nucleotide substitution in the region of this and flanking regions indicate that strong positive selection for amino acid change is operating in the generation of antigenic diversity.

Amino Acid Sequence↗
PubMed1986

Hypervariable region peptides variably induce specific anti-idiotypic antibodies: an approach to determining antigenic dominance.

Rats and rabbits were immunized with synthetic peptides corresponding to the VH hypervariable regions of several alpha (1----3) dextran-specific antibodies from mice to study the efficacy of synthetic peptides in the generation of site-specific anti-idiotypic reagents. Synthetic peptides were made which corresponded to the HV1, HV2, and HV3 hypervariable regions of the heavy chain of M104 (IdX+, IdI-(M104)+), HV2 of HDex 14 (IdX-), and HV3 of J558 (IdX+, IdI(J558)+). The HV1(M104) peptide sequence is found in all dextran-specific immunoglobulins examined and the HV2 and the HV3 peptides span the regions implicated in IdX and IdI expression, respectively. Sera from many rabbits and rats indicate that all five peptides are immunogenic. Antisera to HV3 peptides show excellent binding to the appropriate myeloma proteins, with antisera to the HV3(M104) peptide demonstrating little binding to proteins that differ in HV3 sequence. Antisera generated against HV1(M104) and both HV2 peptides show weak cross-reaction to the appropriate proteins; however, these sera are not idiotypic because they cross-react with immunoglobulins with very limited sequence homology. Thus, it appears that some, but not all synthetic peptides from hypervariable regions will be capable of generating antisera with useful anti-idiotypic specificities. This may reflect differences in the intrinsic antigenicity of various parts of the VH region.

Amino Acid Sequence↗
PubMed1990

Importance of hypervariable regions of HIV-1 gp120 in the generation of virus neutralizing antibodies.

Variants of the envelope gene of the HIV-SF2 isolate of HIV-1 with deletions of one or more of the hypervariable domains of gp120 were produced in genetically engineered yeast as nonglycosylated denatured polypeptide analogs of gp120. Purified antigens were used to immunize experimental animals to determine whether the removal of hypervariable regions from this type of gp120 immunogen had any effect on (1) the ability of the antigen to elicit virus neutralizing antibodies; and (2) the isolate specificity of the neutralizing antibodies that were elicited. The results of these studies demonstrate that, in addition to the previously identified V3 domain, at least two other hypervariable regions in gp120 are capable of eliciting neutralizing antibodies in experimental animals. However, when all five of the hypervariable regions were deleted, the resulting antigen was no longer capable of eliciting neutralizing antibodies. Finally, the neutralizing antibodies elicited by all of these nonglycosylated antigens were effective against HIV-SF2, the isolate from which the antigens were derived, but were not able to neutralize two divergent isolates, HIV-BRU or HIV-Zr6.

Animals↗
PubMed1991

Concept of VNTR alleles: comparison of apolipoprotein B 3' hypervariable region genotyping results obtained by three methods.

In this study the apolipoprotein B 3' hypervariable region genotyping results obtained by three polymerase chain reaction and gel electrophoresis -based methods were compared. In 43 subjects of Finnish origin three individuals had each one allele (3.5%) which exhibited different migration when the apolipoprotein B 3' hypervariable region amplification products were separated on nondenaturing polyacrylamide gel electrophoresis as compared to agarose or denaturing polyacrylamide gels. Segregation of the variantly migrating alleles could be demonstrated in pedigrees suggesting that the variation might be due to differences in the DNA sequence among alleles with same apparent size on agarose or denaturing polyacrylamide gels.

Alleles↗
PubMed1991

Epidemiologically closely related viruses from hemophilia B patients display high homology in two hypervariable regions of the HIV-1 env gene.

The diversity of human immunodeficiency virus type 1 (HIV-1) is mainly caused by mutations that affect the gene encoding the gp120 envelope protein. Isolates differ to a large extent in the hypervariable regions of gp120. This study was undertaken to determine the degree of variation of HIV-1 env genes isolated from seven individuals with hemophilia B who became infected in association with administration of a suspected clotting factor lot. Two hypervariable regions and part of a constant region from proviral DNA of the peripheral blood leukocytes of these patients were amplified and the products of the polymerase chain reactions were sequenced. The sequences derived from five of the individuals displayed 100% sequence homology, 1 had two and 1 had six deviations from the consensus sequence. The alignment of the amino acid sequence so deduced revealed no comparable homology to any of these two hypervariable regions from a number of published isolates. The genetic variability of HIV-1 seems to be limited, at least in the early phase of infection, allowing the determination of close relationships between epidemiologically related strains.

Amino Acid Sequence↗
PubMed1991

Tolerance to a self peptide from the third hypervariable region of the Es beta chain. Implications for molecular mimicry models of autoimmune disease.

As a first step in the analysis of a molecular mimicry model of rheumatoid arthritis, we addressed the question of whether tolerance to self-major histocompatibility complex (MHC) class II molecules includes tolerance to peptides from the third hypervariable region of their beta chain. We studied T cell responses to a peptide from the third hypervariable region of the Es beta chain, Es beta peptide (PEFLEQRRAAVDTYC), in different mouse strains after footpad priming with peptide in complete Freund's adjuvant. Strains of mice of the k or d haplotype (B10D2; H-2d, B10BR; H-2k) mounted a vigorous T cell response to the Es beta peptide. In mice expressing the Es beta chain either on the cell surface (B10S9R) or in the cytoplasm as free unassociated chain (B10S), no response could be detected. Binding studies using purified MHC class II molecules and competition for antigen presentation showed that the Es beta peptide binds Ak, Ad and As but not Ek. Thus, the nonresponder status of B10S and B10S9R mice appears to reflect self tolerance. Tolerance was also suggested by the observation that responder x nonresponder F1 crosses such as (B10D2 x B10S9R) and (B10BR x B10S9R) did not respond to Es beta peptide. Interestingly, mice derived from the (B10BR x B10S) cross responded to the Es beta peptide, suggesting that the immune system may not always tolerate peptides from the third hypervariable region of self-MHC class II molecules.

Amino Acid Sequence↗
PubMed1992

Crucial role of the third and fourth hypervariable regions of HLA-DPB1 allelic sequences in the mixed lymphocyte reaction.

Since HLA-DP mismatches are known to induce proliferative response in MLR I, we investigated the real impact of the different DP alleles and the possible role of one or several hypervariable regions of the DPB allelic sequences. Accordingly, we performed MLR I between HLA-A, B, DR, DQ, and Dw identical individuals DP oligotyped after DNA amplification. A total of 23 one-DP-mismatched healthy stimulator and responder cells displaying nine different DP specificities were thus evaluated in 52 MLRs I. This allowed us to analyze the impact of amino acid composition of each of the six hypervariable regions independently of the amino acid matching or mismatching in the five others. We show here that DP combinations sharing the same amino acid sequence in the third (C) and fourth (D) hypervariable regions are associated with a low proliferative response in vitro (p less than 0.01). These data imply that a perfect HLA-DP matching may not be requisite in selecting bone marrow donors. Indeed, the choice of donors may rely on determination of these particular mismatched HVRs between the DP alleles involved especially in GvHD direction. This policy including prospective DP oligotyping should be of great interest, especially when MLRs I are false negative or nonevaluable. It will enable a better definition of which DP mismatches are acceptable in BMT.

Alleles↗
PubMed1991

Rheumatoid arthritis in Israeli Jews: shared sequences in the third hypervariable region of DRB1 alleles are associated with susceptibility.

Rheumatoid arthritis (RA) is known to be associated with class II HLA antigens in most populations, but recent studies in Israeli Jewish patients showed no significant differences in either DR4 or DR1 between patients and controls. In a previous DR4 subset study we found DR4-Dw15 to be associated with susceptibility (RR = 9.2) but this allele occurred in only 12% of the patients. We analyzed all DRB1 genes, using the polymerase chain reaction (PCR) and hybridization with allele specific oligonucleotides, in 49 Jewish patients with RA and 40 normal Jewish controls. Six DRB1 alleles that are similar to the prototype DR4-Dw4 (DRB1*0401) appeared to contribute to the risk for developing RA. In addition to DR4-Dw15 (DRB1*0405) 2 other alleles having substitutions in codons 71 only (DR1-Dw1/DRB1*0101, DR4-Dw14.2/DRB1*0408) or in codons 70 and 71 (DRw10/DRB1*1001) gave highly significant relative risks. Together, this group, with valine in position 85, and glycine in codon 86, gave a relative risk of 11.0 (p = 0.0002). Two other alleles with the same sequence in the third hypervariable region (amino acids 67-74) but with valine in codon 86 (DR4-Dw14.1/DRB1*0404) or alanine in 85 and valine in 86 (DR1-Dw20, DRB1*0102) gave a combined risk of 3.6 (p = 0.049). Altogether these 7 alleles with similar sequences in the third hypervariable region accounted for 55.6% of the patients, with an overall relative risk of 8.6 (p = 0.00002). Our results in this population indicate that shared epitopes in the third hypervariable region of DRB1 alleles also play a role in susceptibility to RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1989

High-resolution analysis of a hypervariable region in the human apolipoprotein B gene.

A hypervariable region occurs immediately 3' of the human apolipoprotein B gene. Several allelic variants of this tandemly repeated sequence can be resolved by genomic blotting. Higher resolution among size variants may be obtained by polymerase-chain-reaction amplification of this region followed by electrophoresis in a denaturing acrylamide gel. Fourteen different alleles containing 25-52 repeats of the basic 15-bp unit were distinguished in a population study of 318 unrelated individuals. This approach should be applicable to pedigree and linkage analysis with the apolipoprotein B gene or other tandemly repeated sequence elements.

Alleles↗
PubMed1986

Molecular characterisation of a hypervariable region downstream of the human alpha-globin gene cluster.

We have characterised an unusual, highly polymorphic region of DNA located 8-kb downstream of the human alpha-globin gene complex. This hypervariable region (alpha-globin 3' HVR) is composed of an array of 17-bp tandem repeats, the number of which differs considerably (70-450) from one allele to another. The sequence of the 17-bp repeats is highly conserved within and between alleles. Furthermore, this sequence identifies a core oligonucleotide [5'-GNGGGG(N)ACAG-3'] that is common to three previously characterised hypervariable regions. At reduced stringency, a probe to the 3' HVR detects a new family of multiallelic loci that will be of value in the study of human genetics.

Alleles↗
PubMed1990

Constant and hypervariable regions in conotoxin propeptides.

Conotoxins are small cysteine rich peptides found in the venom of the predatory cone snails (Conus) which have prove to be useful high affinity ligands for various receptors and ion channels. The first cloning data for conotoxins, reported here, were obtained for the King-Kong peptide, a 27 amino acid conotoxin found in the venom of the cloth-of-gold cone, Conus textile. Analysis of cDNA clones of the King-Kong peptide revealed a family of related toxin transcripts. Three different propeptide cDNA sequences were obtained; only one of these encoded sequence for the King-Kong peptide. The other cDNA sequences encoded two different peptides (KK-1 and KK-2). When the predicted propeptide sequences are compared, well defined conserved and hypervariable regions can be identified. The hypervariable regions comprise four regions between Cys residues in the final peptide toxins; the remainder of the propeptide sequences, i.e. the excised N-terminal regions and the disulfide bonded Cys residues, are highly conserved. We suggest that the conserved regions may direct the formation of a specific disulfide configuration in the King-Kong family of conotoxins.

Amino Acid Sequence↗