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

Abstract

An internal molecular deletion occurring in a human lambda type immunoglobulin light (L)chain (Sm X) 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 y and X subunits. The Sm A 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 subgoup II. Since XI, 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 that two distinct structural genes encode a single immunoglobulin polypeptide chain.Because of the heterogeneity of the normal immune response, detailed knowledge of the structure of immunoglobulins has been principally derived from the biochemical analyses of the monoclonal immunoglobulins produced in elevated quantities in patients with multiple myeloma, Waldenstrom's macroglobulinemia, and related plasma cell dyscrasias (1-3). Since the immunoglobulins in these disorders are relatively homogeneous, they are thought to represent a minute fraction of the normal immunoglobulin spectrum each animal has the potential to generate. One consequence of the extensive data on Bence Jones and myeloma proteins has been to lend credence to the theory advocated by Abbreviations: The nomenclature and abbreviations for immunoglobulins, their subunits, proteolytic fragments and genetic markers are those recommended by the

The amino acid sequence of a carbohydrate-containing immunoglobulin-light-chain-type amyloid-fibril protein

“…Leu-99 (Kabat et al, 1983). The significance of these residues for the formation of amyloid material is unclear, Composition but most of these amino acid residues have predom-(residues/molecule) inant f-pleated sheet potential (Muckle & Goldsmith, 1980 (Garver & Hilschmann, 1972;Garver 0.6 1.0 3.6 et al, 1975;Kiefer et al, 1980). The AL protein presented glucosamine.…”

Human heavy chain disease protein WIS: implications for the organization of immunoglobulin genes.

“…Starting with residue 12, there is identity with the vy hinge (7). However, residues [1][2][3][4][5][6][7][8][9][10][11] do not correspond to the sequence preceding the 'yS hinge or the homologous region of the 'y1 heavy chain. When the first 11 residues'are compared to various regions of the H chain (Fig.…”

“…Three yl myeloma proteins with internal deletions were recognized because of their dissociability under nonreducing conditions, and it was shown that only the hinge region from residues 216-230 is missing (2-4; L. A. Steiner, personal communication). Two other myeloma proteins with internal gaps in the light (L) chains (SAC and SM) have deletions of much of the variable region; the deletions end at points that may correspond to the VC joining region (5,6).…”

The Effect of Paraprotein on Platelet Aggregation

“…Paraproteins appear as molecules missing certain polypeptide chains, or their parts, as well as hybrid molecules with a variety of oligosaccharide chains, or as molecules with subtle changes without visible effects on the global structure. Structural alterations occur in both light and heavy chains of the paraproteins, as a consequence of genetic (deletions, insertions, conversions, point mutations) or posttranslational changes .…”