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At least 19 recordsLinked to original sources
PubMed1976

Human and murine phosphorycholine-binding immunoglobulins: conserved subgroup and first hypervariable region of heavy chains.

The NH2-terminal 36 residues of the heavy chain and the NH2-terminal 40 residues of the light chain from a human Waldenström's IgM with binding activity for phosphorylcholine (phosphocholine) are compared with the published sequences of five mouse IgA myeloma proteins with the same activity. An extensive structural similarity; i.e., 3 amino acid interchanges within framework residues, and one in the hypervariable region, is noted between the heavy chains of both species. The light chains, however, show a considerable diversity and, in contrast to the heavy chain, no correlation between the primary structure of the first hypervariable region and the binding specificity is apparent. The finding of a very similar heavy chain variable region in two different species that are separated by about 75 million years in evolution favors the concept of stable transmission of variable region genes throughout evolution.

Amino Acid Sequence↗
PubMed1976

Purification, specificity, and hypervariable region sequence of anti-pneumococcal polysaccharide antibodies elicited in a single rabbit.

Four homogeneous antibodies to type VIII pneumococcal polysaccharide (S8) were isolated from the serum of a single rabbit (3322) by affinity chromatography on an S8 immunoadsoebent by utilizing gradient elution with cellobiose and NaCl. The binding properties of these antibodies were determined by a radioimmunoassay with 125I-bovine gamma-globulin-S8. Cellobiose (a disaccharide unit of S8) was the immunodominant group of each of the four antibodies, but each antibody bound to this disaccharide with different relative affinities. The amino acid sequences (positions 0-40) of three of the four antibody light chains were each different both in framework and first hypervariable region sequences. The fourth antibody light chain has a blocked amino terminus. These findings indicate that antibodies elicited by a relatively simple antigen and examined at one time during the course of immunization in a single rabbit may exhibit common specificities for an oligosaccharide determinant, yet have different binding affinities for that determinant as well as different primary structures in the complementarity (hypervariable) regions and framework regions.

Amino Acid Sequence↗
PubMed1992

Characterization of hypervariable regions in the putative envelope protein of hepatitis C virus.

We previously identified two hypervariable regions [HVR1 (27 amino acids) and HVR2 (7 amino acids)] in the putative envelope glycoprotein (gp70) by comparison of the amino acid sequences of many isolates of the HCV-II genotype. To understand the functional features of these HVRs, using the polymerase chain reaction we analyzed the rate of actual sequence variability in the region including HVR1 and HVR2 of HCV isolated successively at intervals of several months from two patients with chronic C-type hepatitis. In both patients, the amino acid sequence of HVR1, but not HVR2, was found to change dramatically during the observation period (about one amino acid per month). However, no alteration of the amino acid sequence of HVR1 of HCV was observed in a patient in the acute phase of chronic hepatitis. Restriction digestion analysis of sequence diversity showed that a HCV genome with a newly introduced mutation in HVR1 often became the predominant population at the next time of examination. Alterations of amino acids in HVR1 occurred sequentially in the two patients in the chronic phase. These findings suggest that mutations in HVR1 are involved in the mechanism of persistent chronic HCV infection.

Alanine Transaminase↗
PubMedDate not supplied

The relationship between hypervariable regions, antigen-binding specificity and the three-dimensional structure of antibodies.

The amino acid sequences of the V domains (VL + VH regions) of 3 antibodies raised to type III pneumococcal polysaccharide in individual outbred rabbits are reported. With the exception of the second hypervariable section of the L chains, these antibodies have very different sequences in the hypervariable segments of the V domains. Within the third hypervariable region of the H chain, each antibody has a different length. On the sole basis of the amino acid sequences of these three anti-pneumococcal antibodies, the results do not support the concept of a simple correlation between primary structure in the hypervariable sections (known to determine the shape of the combining site) and antigen-binding specificity. In view of the large number of amino acid interchanges in the hypervariable positions and because of the size difference between the rabbit H chains, it is likely that each anti-SIII H chain studied here represents the product of a different structural germ line gene. In contrast to such a complex immune response to a relatively simple polysaccharide antigen, an extensive structural uniformity has been observed in the heavy chains of mouse myeloma proteins with phosphorylcholine activity and a mu chain from a human Waldenström IgM endowed with the same activity. The finding of a very similar heavy chain variable region in two different species which are separated by about 75 million years in evolution favours the concept of stable transmission of variable region genes throughout evolution.

Amino Acid Sequence↗
PubMed1992

Linkage between rheumatoid arthritis susceptibility and the presence of HLA-DR4 and DR beta allelic third hypervariable region sequences in southern Chinese persons.

OBJECTIVE: To analyze HLA-DR and DQ associations with rheumatoid arthritis (RA) in patients from southern China. METHODS: In 66 patients and 45 controls, restriction fragment length polymorphism studies were performed using DRB, DQA, and DQB probes, and DRB allele-specific typing of polymerase chain reaction-amplified DRB DNA: RESULTS: The frequency of HLA-DR4 was significantly increased among RA patients (42.4% versus 17.8%). Increased frequencies of the DQA3 allele (77.8% versus 48.9%) and the DQB1*0302 allele (71.0% versus 46.3%), which are in linkage disequilibrium with DR4, were also found. Oligonucleotide typing showed that the amino acid sequence LLEQRRAA, spanning amino acid positions 67-74 of the DR beta molecule, was found in 19 of 49 patients and 5 of 32 controls. The main DR4 allelic subtypes found in the population were DRB1*0404 and DRB1*0405, both of which carried the sequence. There was no difference in subtype distribution between patients and controls. CONCLUSION: Chinese RA patients have an increased frequency of HLA-DR4 alleles which possess the same DRB third allelic hypervariable sequence shown to be associated with susceptibility in Caucasian RA patients.

Alleles↗
PubMed1992

Entamoeba histolytica extrachromosomal circular ribosomal DNA: analysis of clonal variation in a hypervariable region.

The ribosomal RNA genes of the protozoan parasite Entamoeba histolytica are highly repeated and display restriction fragment length polymorphism. Using a set of four DNA probes spanning the coding region and part of the flanking region of the E. histolytica ribosomal RNA genes, an analysis of the DNA bands generated by EcoRI digestion of Entamoeba DNA is presented. This analysis included five strains of E. histolytica, four strains of E. moshkovskii, and one strain each of E. invadens and E. terrapinae. No common bands were observed between E. histolytica and the other Entamoeba. Within E. histolytica, two bands were conserved in all strains while the others were polymorphic. Detailed analysis of DNA from independently isolated clones of the strain HM-1:IMSS of E. histolytica showed two bands to be highly polymorphic. Of these, the 4.4-kb band of clone 6 was further analyzed. Polymorphism in this band could even be demonstrated in cells of the same clone. Restriction enzyme analysis of this DNA band from two clones of HM-1:IMSS showed that the polymorphism may be due to variable numbers of DraI repeat units present in this DNA stretch.

Animals↗
PubMed1992

Peptide sequences from the hypervariable regions of two monoclonal anti-idiotypic antibodies against the thyrotropin (TSH) receptor are similar to TSH and inhibit TSH-increased cAMP production in FRTL-5 thyroid cells.

Monoclonal antibodies, D2 and 4G11, selected by the autoantiidiotypic approach following injection of thyrotropin (TSH) into mice, mimic TSH in binding to receptors on thyroid membranes. Based on TSH receptor transfection studies, D2 and 4G11 show unequivocal specificity for the TSH receptor. To see if the complementary determining regions (CDRs) of these antibodies share any primary sequence similarities to regions of TSH critical for receptor binding, we deduced the primary structure of the variable regions of D2 and 4G11 by sequencing the immunoglobulin mRNA. We found that CDR1 of 4G11K and CDR2 of D2 mu show sequence similarity to regions of TSH alpha and TSH beta that had been previously implicated in the interaction of the hormone with its receptor. We tested the inhibitory effects of synthetic peptides from D2 mu-CDR2 and 4G11K-CDR1 on the binding of the corresponding antibodies to rat thyroid FRTL-5 cells and found an EC50 of 0.1 and 1 microM, respectively. TSH-derived peptides with similarity to D2 mu-CDR2 and 4G11K-CDR1 showed a significant but lesser effect on the binding of 4G11 or D2 to thyroid cells. Additionally, we tested the effects of the CDR peptides and TSH-derived peptides on TSH-stimulated cAMP production in FRTL-5 cells and found that D2 mu-CDR2 and 4G11K-CDR1 inhibited this activity, D2 mu-CDR2 most strongly (EC50 10 microM). Thus, linear sequences from the CDRs of these autoantiidiotypic antibodies with similarity to sequences from both subunits of TSH appear to interact with the TSH receptor. These data support previous studies indicating the complexity of the interaction between TSH and its receptor and advance earlier findings that such immunologic approaches are useful in dissecting receptor-ligand interactions.

Animals↗
PubMed1978

Sequence of a mouse germ-line gene for a variable region of an immunoglobulin light chain.

We have determined the sequence of the DNA of a germ-line gene for the variable region of a mouse immunoglobulin light chain, the VlambdaII gene. The sequence confirms that the variable region gene lies on the DNA separated from the constant region. Hypervariable region codons appear in the germ-line sequence. A sequence for the hydrophobic leader, 19 amino acids that are cleaved from the amino terminus of the protein, appears near, but not continuous with, the light chain structural sequence: most of the leader sequence is separated from the rest of the gene by 93 bases of untranslated DNA.

Animals↗
PubMed1976

Complete amino acid sequence of the variable domains of two human IgM anti-gamma globulins (Lay/Pom) with shared idiotypic specificities.

On the basis of extensive shared idiotypic specificities, two human IgM anti-gamma-globulins (Lay/Pom) were selected for complete amino acid sequence analysis of their variable domains. Previous studies on the variable regions of the heavy chains of these proteins had shown but eight amino acid differences, only one of which was within a complementarity-determining hypervariable region. The complete amino acid sequence of the variable regions of the light chains of these two proteins is the subject of this report. Protein Lay is a typical VchiI protein with only five 'framework' differences when compared with protein Roy. Protein Pom is best classified as a VchiII, but in the 'framework' there are 16 differences between it and protein Ti. Although there are extensive differences in the first hypervariable region, the second and third light-chain hypervariable regions have an identical sequence. The finding of two identical light-chain and two identical heavy-chain hypervariable regions in these two proteins, which were selected on the basis of their combining specificities and their idiotypic cross-reactions, strongly implicates hypervariable regions in the constitution of the idiotypic determinants and the antibody combining site. Additionally, the finding of identical hypervariable regions in light chains of different V-region subgroups fulfills a prediction of the gene-interaction concept of antibody variability.

Amino Acid Sequence↗
PubMed1975

Diversity of light chain variable region sequences among rabbit antibodies elicited by the same antigens.

We report the complete variable region sequences of three homogeneous rabbit antibody light chains and the partial sequences of five others. Wehn these are compared to other published rabbit light chain sequences, two regions of markedly increased variability are revealed, which are homologous in position to the first and third hypervariable regions of murine and human myeloma light chains. In addition, there is increased variability among the first three residues at the aminoterminal end. A hypervariable region homologous to that identified at positions 50 to 56 in myeloma light chains is not present in these rabbit antibody light chains. The available three-dimensional models of Fab fragments based on x-ray crystallography indicate that neither the amino-terminal portion of the light chain nor the region homologous to positions 50 to 56 forms a part of the combining site. Comparison of the hypervariable regions among six light chains from antibodies to Type III pneumococcal polysaccharide and among four from antibodies to Type VIII pneumococcal polysaccharide suggests that a large number of different sequences may be found in antibodies specific for these relatively simple antigens. Certain residues outside of the hypervariable regions are invariant in the rabbit light chains and correspond to residues that are required for proper chain folding in human and murine myeloma light chains, indicating that the general conformation of myeloma light chains is the same as that of light chains of elicited antibodies.

Amino Acid Sequence↗
PubMed1975

Structural studies on induced antibodies with defined idiotypic specificities. I. The heavy chains of anti-p-azophenylarsonate antibodies from A/J mice bearing a cross-reactive idiotype.

Amino acid sequence analysis has been performed on three groups of heavy (H) chains of A/J mice. H chains derived from unimmunized animals were compared to anti-p-azophenylarsonate (anti-Ar) antibodies which were further subdivided into those possessing and those depleted of a cross-reacting idiotype (CRI). It was found that anti-Ar antibodies bearing the CRI are homogeneous through the first hypervariable region of the H chain. The same sequence was obtained for pooled antibody isolated from the ascites fluid of 18 A/J mice or from a single mouse. The H chains appear to belong to a minor V-H subgroup. In the first 30 positions Anti-Ar antibodies depleted of the CRI had the same sequence as those containing the CRI (with small amounts of heterogeneity at some positions), but contained a mixture of sequences in the first hypervariable region of the H chain. These studies indicate that antibodies with similar specificity and with identical framework sequences, but which differ in their hypervariable regions, contain different idiotypic determinants, and support the concept that the idiotypic determinants reside primarily within hypervariable regions.

Amino Acid Sequence↗
PubMed1977

Primary structure of the variable regions of two canine immunoglobulin heavy chains.

The complete amino acid sequences of the variable regions of two canine immunoglobulin heavy chains have been determined by automated Edman degradation and found to be strongly homologous to the human VHIII subgroup. The canine sequences were identical with each other at 76 of 113 residue positions. Twenty-three of the 37 differences are located within the four hypervariable regions previously defined by the sequences of several human VHIII proteins. Forty-five of 77 framework residue positions are invariant in the seven human and two canine VHIII proteins which have been completely sequences. The canine proteins are 78% homologous to the framework of the human prototype. Phylogenetically associated residues before the first hypervariable region were confirmed and several potential phylogenetically associated residues were identified between the first and third hypervariable regions. This study represents the first complete amino acid sequences of VH regions of spontaneously occurring, nonhuman homogeneous immunoglobulins. The date demonstrate a high degree of preservation of VHIII structure in another species.

Amino Acid Sequence↗
PubMed1976

Amino acid sequence of rabbit light chains: variable region of a light chain from a homogeneous immunoglobulin raised by streptococcal immunization.

The variable region sequence has been determined for the light chain (L) from a rabbit homogeneous immunoglobulin (3547) produced by immunization with group A streptococcal vaccine. Unlike most immunoglobulins produced by these vaccines, this immunoglobulin had no binding activity for the group A polysaccharide nor for any of a wide range of streptococcal cell components tested, nor did it have binding activity for rabbit IgG. Tryptic digestion of the citraconylated L chain and acid hydrolysis of the aspartyl-proline bond at positions 109-110 were used to obtain two variable region peptides comprising residues 1-61 and 62-109, respectively. Automated sequence analysis of these peptides and the peptides obtained from them by complete tryptic digestion gave sequence data for the entire L-chain variable (V) region. Comparison of the 3547 L chain V region sequence with other data supports the observations that only two hypervariable regions are present in rabbit kappa chains and that the hypervariable region beginning at residue 90 may vary in length by as much as six residues.

Amino Acid Sequence↗
PubMed1975

Primary structure of a deleted human lambda type immunoglobulin light chain containing carbohydrate: protein Sm lambda.

An internal molecular deletion occurring in a human lambda type immunoglobulin light (L)-chain (Sm lambda) has been defined by sequence analysis. The Sm protein was isolated from the urine of a patient with a plasma cell dyscrasia involving the synthesis of an IgG molecule with both deleted gamma and lambda subunits. The Sm lambda polypeptide chain has an approximate molecular weight of 15,000 and contains 135 amino-acid residues. The constant (C) region is fully intact, comprising 105 residues, whereas the variable region (V) has only 30 residues. The V-region segment represents residues 1 through 30 of normal lambda chains and possesses considerable homology (87%) to lambda chains of subgroup II. Since lambdaII proteins normally contain 216 amino-acid residues, the defect represents an intramolecular deletion of 81 residues, which is entirely confined to the carboxyterminal three-quarters segment of the V-region, with a resumption of normal synthesis at a glutaminyl residue at position 110, the initiation point of the C-region. Carbohydrate is attached to an Asx residue at position 25, in the first hypervariable region, associated with the sequence triplet Asx-Ser-Ser, which is postulated to be a common recognition site for glycosylation of immunoglobulins. The carbohydrate moiety is a complex oligosaccharide with a branched chain structure containing sialic acid, fucose, mannose, N-acetylglucosamine, and galactose. These structural studies and other findings suggest that restricted areas in the DNA of immunoglobulin genes, such as the hinge regions of heavy (H) and light (L) chains and the hypervariable regions, are particularly susceptible to breakage and reunion. We postulate that the genetic defect of protein Sm could have originated from a somatic mutational event in the plasmacyte precursor during or after the integration of the V and C genes. These studies provide additional support for the hypothesis and two distinct structural genes encode a single immunoglobulin polypeptide chain.

Amino Acid Sequence↗
PubMed1976

Rabbit antibody light chains: selective breeding narrows variability in framework and complementarity-determining residues.

The amino acid sequence of 5 light (L) chain (b4) variable (Vl) regions and the partial sequence of VL (kappa) regions from 12 anti-streptococcal group A-varant polysaccharide (Av-CHO) and 2 anti-streptococcal group C polysaccharide (C-CHO) antibodies was determined. These sequences contain 70 invariant positions as opposed to 50 invariant positions in other rabbit VL regions. Variability within the framework residues lacks randomness, and parent offspring relationship or otherwise close familial relationship is apparent in several instances. Variability in the complementarity-determining regions is reduced by 2.3-5.5-fold in comparison with other rabbit L-chains with several identical first and third hypervariable regions. Residue positions 50-56, known to mark the second hypervariable region in human kappa-chains, are not hypervariable in L-chains from Av-CHO rabbit antibodies. Considering the 67 rabbit L-chain sequences, completely or partially known today, for counting the number of V region germ line genes, it is concluded that the species rabbit has at least 27 VL germ line genes available.

Amino Acid Sequence↗