Interchain and Intrachain Disulfide Bridges of a Human Immunoglobulin M: Detection of a Unique Fragment

Frangione, Blas; Prelli, Frances; Mihaesco, Constantin

doi:10.1073/pnas.68.7.1547

Cited by 15 publications

(5 citation statements)

References 20 publications

(23 reference statements)

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“…Structural studies of human myeloma proteins belonging to each of the major classes and subclasses of immunoglobulins have clearly defined four or more domains or homology regions that bear striking homologies to each other, suggesting that they have evolved by a series of gene duplications (1)(2)(3). An exception to this is the "hinge" region, a fragment of about 20 residues in the center of the heavy chains that bears no homology to any other region of either light or heavy chains.…”

mentioning

confidence: 99%

Partial Duplication in the “Hinge” Region of IgA ₁ Myeloma Proteins

Frangione

Wolfenstein‐Todel

1972

Proc. Natl. Acad. Sci. U.S.A.

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The aminoacid sequence of the "hinge" region of two human IgAl myeloma proteins was found to be identical. A 30-residue fragment contains 3 cysteines, 12 prolines, and carbohydrate, and the sequence of a small segment of the hinge region is repeated at least twice. Since a deletion of 12-13 residues was found in the same region of an IgA2 myeloma protein, it is possible that IgAi molecules are the result of the insertion of a partially duplicated gene segment in the immunoglobulin genes.

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mentioning

confidence: 99%

Partial Duplication in the “Hinge” Region of IgA ₁ Myeloma Proteins

Frangione

Wolfenstein‐Todel

1972

Proc. Natl. Acad. Sci. U.S.A.

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“…Both the attachment of J chain and the pronounced homology between the C-terminal sequences of a and a chains suggest intersubunit linkage at the penultimate half-cystines. On the other hand, the half-cystines alkylated after limited reduction of the pentamer have been located at position 414 in the /r chain rather than at the penultimate 575 position (Beale and Feinstein, 1969;Frangione et al, 1971;Putnam et al, 1973).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the available data do not establish the exact location of the monomer-monomer bonds. A half-cystine in the Ch3 domain of the ix chain is alkylated after limited IgM reduction (Beale and Feinstein, 1969;Frangione et al, 1971;Putnam et al, 1973), but it is not clear whether the residue is directly involved in intersubunit bonding or whether it is modified as a result of disulfide interchange during reductive cleavage.…”

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confidence: 99%

Linkage and assembly of polymeric IgA immunoglobulins

Chapuis¹,

Koshland²

1975

Biochemistry

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The intersubunit linkage of polymeric IgA immunoglobulins was determined from studies of the products of reductive and cyanogen bromide cleavage. Under conditions of limited dithioerythritol reduction tetramer IgA molecules were cleaved to yield two monomers and a J chain containing dimer. The stability of the dimer and the conservation of the J chain disulfides indicated that the J chain joins two monomer subunits. Evidence confirming the J chain dimer clasp was obtained from the depolymerization of tetramer and dimer IgA by cyanogen bromide treatment. The cleavage studies also showed that (a) the S-S bonds directly joining the other subunits are located at the same penultimate alpha chain half-cystines that constitute the site of J chain attachment and (b) during limited reduction the monomer-monomer bonds undergo interchange to release subunits without a concomitant generation of alpha chain thiols. These linkage data provide strong support for the assembly of IgA and IgM polymers by sequential disulfide exchanges beginning with the formation of a J chain containing dimer.

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“…The thyroglobulin and/or the wild-type CdtA-His 6 subunit protein was treated with a reducing buffer containing 10 mM DTT, 4 M guanidine-HCl, and 10 mM Tris-HCl (pH 8.5) for 10 min at room temperature (15). Separate ELISA plates were first coated with reduced and unreduced thyroglobulin.…”

Section: Methodsmentioning

confidence: 99%

Role of Intrachain Disulfides in the Activities of the CdtA and CdtC Subunits of the Cytolethal Distending Toxin ofActinobacillus actinomycetemcomitans

Cao

Volgina²,

Korostoff

et al. 2006

Infect Immun

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The cytolethal distending toxin (Cdt) of Actinobacillus actinomycetemcomitans is an atypical A-B-type toxin consisting of a heterotrimer composed of the cdtA, cdtB, and cdtC gene products. The CdtA and CdtC subunits form two heterogeneous ricin-like lectin domains which bind the holotoxin to the target cell. Point mutations were used to study CdtC structure and function. One (mutC216 F97C ) of eight single-amino-acid replacement mutants identified yielded a gene product that failed to form biologically active holotoxin. Based on the possibility that the F97C mutation destabilized a predicted disulfide, targeted mutagenesis was used to examine the contribution of each of four cysteine residues, in two predicted disulfides (C96/C107 and C135/ C149), to CdtC activities. Cysteine replacement mutations in two predicted disulfides (C136/C149 and C178/ C197) in CdtA were also characterized. Flow cytometry and CHO cell proliferation assays showed that changing either C96 or C149 in CdtC to alanine abolished the biological activity of holotoxin complexes. However, replacing C107 or C135 in CdtC and any of the four cysteines in CdtA with alanine or serine resulted in only partial or no loss of holotoxin activity. Changes in the biological activities of the mutant holotoxins correlated with altered subunit binding. In contrast to elimination of the B chain of ricin, the elimination of intrachain disulfides in CdtC and CdtA by genetic replacement of cysteines destabilizes these subunit proteins but not to the extent that cytotoxicity is lost. Reduction of the wild-type holotoxin did not affect cytotoxicity, and the reduced form of wild-type CdtA exhibited a statistically significant increase in binding to ligand. A diminished role for intrachain disulfides in stabilizing CdtA and CdtC may have clinical relevance for the A. actinomycetemcomitans Cdt. The cdt gene products secreted by this pathogen assemble and bind to target cells in periodontally involved sites, which are decidedly reduced environments in the human oral cavity.

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Interchain and Intrachain Disulfide Bridges of a Human Immunoglobulin M: Detection of a Unique Fragment

Abstract: Studies of the amino acid sequences around half-cystine residues in an immunoglobulin M have revealed an unexpectedly high number. At

Cited by 15 publications

References 20 publications

Partial Duplication in the “Hinge” Region of IgA ₁ Myeloma Proteins

Partial Duplication in the “Hinge” Region of IgA ₁ Myeloma Proteins

Linkage and assembly of polymeric IgA immunoglobulins

Role of Intrachain Disulfides in the Activities of the CdtA and CdtC Subunits of the Cytolethal Distending Toxin ofActinobacillus actinomycetemcomitans

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Interchain and Intrachain Disulfide Bridges of a Human Immunoglobulin M: Detection of a Unique Fragment

Abstract: Studies of the amino acid sequences around half-cystine residues in an immunoglobulin M have revealed an unexpectedly high number. At

Cited by 15 publications

References 20 publications

Partial Duplication in the “Hinge” Region of IgA 1 Myeloma Proteins

Partial Duplication in the “Hinge” Region of IgA 1 Myeloma Proteins

Linkage and assembly of polymeric IgA immunoglobulins

Role of Intrachain Disulfides in the Activities of the CdtA and CdtC Subunits of the Cytolethal Distending Toxin ofActinobacillus actinomycetemcomitans

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Partial Duplication in the “Hinge” Region of IgA ₁ Myeloma Proteins

Partial Duplication in the “Hinge” Region of IgA ₁ Myeloma Proteins