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At least 19 recordsLinked to original sources
PubMed1976

Conformational isomerism, rotational allomerism, and divergent evolution in immunoglobulin light chains.

Immunoglobulin light chains are examples of single polypeptide chains synthesized under the control of two genes. The three-dimensional structure of a human (Mcg) lambda-type chain (Bence-Jones) dimer supports the hypothesis of a common primordial gene for the amino ("variable" or V) and carboxyl ("constant" or C) halves of each monomer. However, sequence homologies have been obscurred by divergent evolution of the V and C regions ("domains"). The types of evolutionary changes that have occurred in the domain can be surmised by a comparison of the sequences, using the three-dimensional structures as a basis for alignment. Despite substantial differences in sequences, the hydrophobic character of key internal sites has been maintained in each domain. Regions present in only one domain are situated in position appropriate for their functions, but not deleterious to the general structural integrity of a common fold. The divergence of the V and C domains can be interpreted in terms of rotational allomerism. The cylinders of beta-pleated sheets have rotated in such a way that homologous regions in the two domains perform different functions in their interactions with a second molecule of light or heavy chain. These regions include complementarity-determining sites for antigen binding in the V domains and crossover sites stabilizing dimer formation in the C domains. Differences in surface properties between the V1-V2 and C1-C2 dimeric modules may partially explain why the V regions have been implicated in the formation of amyloid fibrils and in the characteristic thermal behavior of Bence-Jones proteins.

Amino Acid Sequence↗
PubMed1978

Guinea pig immunoglobulin light chain isotypes. I. Separation of kappa and lambda chains and the identification of three isotypes of the lambda chain constant homology region.

The separation of intact kappa chain and two fragments comprising lambda (lambda) chain from immunoglobulin light chain pools isolated from strain 13 guinea pigs is achieved by cyanogen bromide digestion and gel filtration before and after reductive clevage of disulfide bonds. The smaller lambda chain fragment derives from the original carboxyl-terminus of lambda chain. The partial sequence of component tryptic and thermolytic peptides of this thirty-nine residue fragment allowed its complete sequence to be deduced. Three isotypic forms of this lambda chain constant region fragment, distinguished by four residue positions showing alternative amino acids, are found expressed by guinea pigs. Each of these three isotypes is more homologous to the other two than to lambda chains of any other species. The distribution of amino acid substitutions differentiating these isotypes further supports the view that lambda chain isotypes arose in guinea pigs, and in several other species, independently by gene duplication.

Amino Acids↗
PubMed1978

Mechanism of antigen-induced antibody biosynthesis from antibody precursors, the heavy and light immunoglobulin chains.

The immediate precursors of antibody molecules, the heavy (H) and light (L) peptide chains of the immunoglobulins, combine with each other by means of disulfide bonds formed by dehydrogenation of their cysteine residues. In the absence of an antigen this process yields the heterogeneous mixture of normal immunoglobulins. Antigens or their processed derivatives (Ag) interfere with this stochastic process by noncovalent combination with complementarily fitting H chains. The (Ag.H)(n) complexes thus formed, owing to the loss of rotational and translational freedom, combine preferentially with those L chains whose V(L) regions have some affinity for the determinants of the antigen molecule. Subsequent release of Ag from the (Ag.H.L)(n) complexes yields free antigen and antibody molecules. Each of the released Ag molecules can be used repeatedly for the same reaction cycle and thus can induce the biosynthesis of a large number of antibody molecules. Any macromolecule, natural or synthetic, that has at least a few polar groups and that can penetrate to the nascent H and L chains can thus act as an antigen. Whereas the structure of the H and L chains is genetically determined and transmitted through the germ line, the process induced by the antigen is a phenotypic phenomenon. The antigen acts in this process as a stereospecific cofactor or regulator of the thiol-disulfide transhydrogenation of the combining H and L chains of immunoglobulins.

Antibody Formation↗
PubMed1978

Acute renal failure associated with a malignant lymphoproliferative disorder with monoclonal light chain immunoglobulin production. Report of a case.

A case of a 32-year-old male negro is reported in whom acute renal failure was the first manifestation of a diffuse lymphocplasmocytic infiltrative disorder. The malignant cells only produced immunoglobulin light chain (lambda-type). A description of the pathological findings is given. The case presented can be considered an intermediate form between macroglobulinaemia and multiple myeloma.

Acute Kidney Injury↗
PubMed1978

The synthesis and processing of the messenger RNAs specifying heavy and light chain immunoglobulins in MPC-11 cells.

The nuclear precursors of the immunoglobulin messenger RNAs of MPC-11 cells were characterized with respect to size, amount per cell and extent of polyadenylation. These cells produce three Ig mRNAs: a 1.8 kb component coding for a gamma2b heavy chain (H mRNA), a 1.2 kb mRNA coding for a k light chain (L mRNA) and a 0.8 kb mRNA coding for the constant region portion of the k light chain (Lf mRNA). To identify the pre-mRNAs without ambiguity, we constructed recombinant DNA plasmids containing H and L cDNA sequences, and used the cloned cDNAs as hybridization probes for analysis of steady state nuclear RNA and in DNA excess hybridization experiments with pulse-labeled nuclear RNA. The nuclear molecules containing Ig sequences consist of an 11 kb component (H1), which we believe to be the primary transcript of the H gene, 5.3 kb (L1), and 3.3 kb (L2) components, which seem to be primary transcripts of the L and L1 genes, components corresponding to mature size H, L and Lf mRNAs, and several intermediate-sized components which include the processing derivatives. The precursor role of these nuclear molecules was established by studies of their labeling kinetics and by appropriate pulse-chase experiments. All the pre-mRNA species including H1, L1 and L2 contain poly(A), thus suggesting that polyadenylation is an early event in the processing of these mRNAs. The MPC-11 cell contains about 30,000 and 40,000 cytoplasmic H and L mRNA molecules, respectively, which must be produced within one cell generation (approximately 24 hr). In comparison, the nucleus contains about 100-150 molecules of total pre-mRNA and only about 10-15 molecules of presumptive primary transcripts for each of these Ig species. These values indicate very rapid transcription rates (greater than 20 transcripts per min) and exceptionally fast processing rates (approximately 0.5 min for the primary transcripts and approximately 5 min for overall nuclear processing) for the Ig mRNAs. Thus rapid transcription and processing, together with high cytoplasmic stability, account for the high abundance of Ig mRNAs in the myeloma cell.

Animals↗
PubMed1979

An allotypic marker on chicken immunoglobulin light chains.

The first chicken immunoglobulin light (L) chain allotypic specificity (L-1.1) to be described that was present on IgM, 7S Ig, Fab, and L chains was detected by radioimmunoassay. The gene controlling the expression of L-1.1 is inherited in a simple Mendelian fashion at an autosomal locus and is unlinked to a constant region heavy chain locus, four blood group loci and three loci determining lymphocyte cell surface alloantigens.

Animals↗
PubMed1978

Guinea pig immunoglobulin light chain isotypes. II. The preferential expression of lambda chain-bearing anti-phenyltrimethylammonium antibodies is associated with restricted variable region expression, but not with any alteration in the proportion of lambda chain constant region isotypes, relative to normal immunoglobulins.

The inbred strain 13 guinea pig expresses at least three isotypes of immunoglobulin (Ig) lambda chain. The proportion of these isotypes in normal Ig can be estimated by isolating a constant (C) region cyanogen bromide peptide from lambda chains and quantitatively analyzing its component tryptic peptides. Anti-phenyltrimethylammonium antibody, when analyzed in this way, was found to contain the same proportion of each lambda chain C region isotype as did normal Ig. The specific antibody light (L) chain pools were found to contain predominantly lambda chains, although these are the minority type in guinea pig normal Ig L chain pools. Moreover, amino-terminal, 5-pyrrolidone-2-carboxylic acid-containing peptides isolated from antibody lambda chains show no demonstrable sequence heterogeneity, while their homologs isolated from normal lambda chains are markedly heterogeneous. That a restriction in heterogeneity of variable region framework residue positions is not associated with any alteration in the proportion of C region isotypes in these antibody lambda chains, implies that translocation of all guinea pig lambda chain variable region genes to the isotypic C region genes occurs in a random way.

Animals↗
PubMed1979

Characteristics of renal handling of human immunoglobulin light chain by the perfused rat kidney.

1. The renal handling of purified human immunoglobulin light chain has been studied with an isolated perfused rat kidney preparation. 2. Human immunoglobulin light chain was freely filtered and largely reabsorbed. Fractional reabsorption was characteristic for each of four light chains and varied between 56% and 86%. No renal tubular maximum for human light chain was obtained. 3. Light chains at concentrations up to 10 times those seen in human myeloma were without effect on glomerular filtration rate or sodium and potassium reabsorption in experiments lasting up to 2 h. 4. Filtered and reabsorbed light chain returned ultimately to the perfusion medium, indicating a unique property of the tubular handling of this protein. None of the inhibitors tested (ouabain, frusemide, acetazolamide, probenicid) influenced light chain reabsorption. 5. The results are taken to indicate that light chain reaches the site of the transport enzyme, Na+,K+-dependent ATPase, at concentrations which vary with the nature of the light chain. This may provide a mechanism for renal damage in patients with myeloma, after prolonged exposure.

Absorption↗
PubMedDate not supplied

[Participation of rat immunoglobulin light chains of the kappa and lambda type in formation of antibodies to the polysaccharide of group A streptococcus].

The role of light kappa and lambda chains and also allelic variants of kappa chains of rat immunoglobins in the formation of antibodies to beta-N-acetyl-glucosamine polysaccharides of streptococcus group A of inbred rat strains MSU, WAG, August and hybrids of the first generation (MUS X WAG)F1 and (MSU X August)F1 was studied. From individual sera of immune rats fractions of specific antibodies to beta-N-acetyl-glucosamine were isolated. These antibodies differ in their affinity to antigenes. The retio of molecules with kappa and lambda light chain types was determined for the fraction of specific antibodies. The ratio of molecules kappa and lambda depends on the affinity of antibodies to beta-N-acetyl-glucosamine and on the genotype of the animals studied. Data obtained allow to conclude that differences in the functional activity of lambda chains between strains WAG and August, on one hand, and strain MSU, on the other, do exist. Functional differences releaved between these rat strains were confirmed by analyzing corresponding antibody fractions to beta-N-acetylglucosamine in F1 hybrids. Differences between allelic variants of kappa chains in the formation of antibodies to beta-N-acetylglucosamine of polysaccharides were not found.

Acetylglucosamine↗
PubMed1979

Mutations affecting immunoglobulin light chain secretion by myeloma cells. I. Functional analysis by cell fusion.

Two clones of MOPC 315 cells have been selected which synthesize but do not secrete Ig lambda light chains. These clones were analyzed by fusion with a cell line synthesizing and secreting kappa chains. Conditions were established for recovery at high frequency (approximately 10(-3)) of spontaneously fused, viable hybrid cells. The resulting hybrid cell lines synthesized both kappa and lambda chains but secreted only kappa chains. Hybrid cells produced by fusion of a lambda-secreting clone of MOPC 315 with the kappa-secreting cell line were also isolated and shown to synthesize and secrete both kappa and lambda chains. These results suggest that the nonsecretion of lambda chains was not due to a defect the secretion mechanism of the variant cells. A more likely alternative is that the lambda chains in the variant cell lines were structurally altered to a form which could not be secreted.

Animals↗
PubMed1977

De novo synthesis and glycosylation of the MOPC-46B mouse immunoglobulin light chain in cell-free extracts.

The mRNA for the mouse MOPC-46B K chain, a glycorportein, was prepared translated in Ehrlich ascites cell-free extract. A polypeptide product similar to the MOPC-46B kappa chain was identified by its antigenic properties and by analysis of the products of tryptic digestion. In addition, the cell-free product was glycosylated after translation. It appeared that glycosylation of the cell-free product occurred on the same tryptic peptide glycosylated by intact cells. The characteristics and requirements of glycosylation are described. The presence of Mn2+ was a major requirement.

Animals↗
PubMed1975

Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma.

Fractionation of MOPC 41 DL-1 tumors revealed that the mRNA for the light chain of immunoglobulin is localized exclusively in membrane-bound ribosomes. It was shown that the translation product of isolated light chain mRNA in a heterologous protein-synthesizing system in vitro is larger than the authentic secreted light chain; this confirms similar results from several laboratories. The synthesis in vitro of a precursor protein of the light chain is not an artifact of translation in a heterologous system, because it was shown that detached polysomes, isolated from detergent-treated rough microsomes, not only contain nascent light chains which have already been proteolytically processed in vivo but also contain unprocessed nascent light chains. In vitro completion of these nascent light chains thus resulted in the synthesis of some chains having the same mol wt as the authentic secreted light chains, because of completion of in vivo proteolytically processed chains and of other chains which, due to the completion of unprocessed chains, have the same mol wt as the precursor of the light chain. In contrast, completion of the nascent light chains contained in rough microsomes resulted in the synthesis of only processed light chains. Taken together, these results indicate that the processing activity is present in isolated rough microsomes, that it is localized in the membrane moiety of rough microsomes, and, therefore, that it was most likely solubilized during detergent treatment used for the isolation of detached polysomes. Furthermore, these results established that processing in vivo takes place before completion of the nascent chain. The data also indicate that in vitro processing of nascent chains by rough microsomes is dependent on ribosome binding to the membrane. If the latter process is interfered with by aurintricarboxylic acid, rough microsomes also synthesize some unprocessed chains. The data presented in this paper have been interpreted in the light of a recently proposed hypothesis. This hypothesis, referred to as the signal hypothesis, is described in greater detail in the Discussion section.

Animals↗
PubMedDate not supplied

[Insertion of mouse kappa light chain immunoglobulin gene sequences into a bacterial plasmid].

The 14S mRNA from MOPC 173 tumour has been transcribed into cDNA by AMV DNA polymerase and converted into a double stranded form by Escherichia coli DNA polymerase I. After addition of oligo-dG tracts at the 3'-OH ends by calf thymus terminal transferase this DNA was hybridized to an E. coli plasmid (pCR1) to which oligo-dG tracts had been similarly added. Circular molecules resulting from GC base pairing have been used to transform C 600 E. coli cells and to confer kanamycine resistance. Several recombinants have been obtained containing the V+C regions and the C or V region alone. These recombinant molecules are being used to analyse the translocation of V and C genes and to purify V and C genes from DNA of germ line cells and of differentiated tumour.

Animals↗
PubMed1976

Reiteration frequency of immunoglobulin light chain genes: further evidence for somatic generation of antibody diversity.

Methods have been developed for preparing mouse immunoglobulin light chain mRNA of better than 90% purity. Hybridization of both lambda and kappa mRNAs to excess liver DNA yielded results compatible with gene reiteration frequencies of two to three. There was no evidence of hybridization of these highly purified mRNAs to reiterated DNA, and, in fact, the kinetics of hybridization were very similar to that of purified globin mRNA. Purified lambda mRNA from tumors producing structurally different lambda chains were used in competition hybridization experiments. An unlabeled lambda mRNA competed with another, labeled lambda mRNA to the same extent as homologous unlabeled lambda mRNA. That is, base sequence homology among lambda mRNAs is so high that any lambda mRNA should cross-hybridize with all germ line variable (Vlambda) genes at least for those V-regions which are represented among myelomas. From amino-acid sequence data, it is argued that there are probably more than 25 different lambda V regions. Hence it is concluded that the number of germ line genes is too small to account for the diversity of lambda chains. A similar conclusion is drawn for kappa chains.

Antibody Formation↗
PubMed1977

Thermodynamic and conformational studies on an immunoglobulin light chain which reversibly precipitates at low temperatures.

A lambda light chain, isolated from an immunoglobulin G molecule, was found to reversibly precipitate at low temperatures. This cryoprecipitation was a function of pH, ionic strength, protein concentration, and time as well as temperature. The lambda chain underwent a cooperative conformational change as the temperature was lowered from 26 to 0 degrees C as judged by ultraviolet difference spectroscopy and circular dichroism. Normal lambda chains showed no conformational change. By difference spectroscopy it was possible to calculate the equilibrium constant governing the conformational change. The change was strongly exothermic (delta H approximately -80 kcal mol-1) and accompanied by a large decrease in entropy (delta S approximately -280 eu). The midpoint of the transition was dependent on the initial protein concentration, suggesting that only the noncovalent dimer of the lambda chain exhibited the conformational change. The existence of a monomer-dimer eqiulibrium (KA approximately 4 X 10(5) M-1) was confirmed by sedimentation velocity. No conformational change was observed by circular dichroism at concentrations where greater than 95% of lambda chain was in the form of a monomer. Although high ionic strength inhibited cryoprecipitation, it had no effect on the conformational change. Stabilization of the dimer by forming an interchain disulfide bond between two monomers abolished both the conformational change and cryoprecipitation. A fragment corresponding to the constant region was isolated from both peptic and tryptic digests of the lambda chain. This fragment neither cryoprecipitated nor showed temperature dependence conformational changes. It proved impossible to isolate a fragment corresponding to the variable region. Both qualitative and quantitative models are presented to account for the behavior of the lambda chain at low temperatures.

Humans↗