Independent expression of the gene coding for the constant domain of immunoglobulin light chain: Evidence from sequence analyses of the precursor of the constant region polypeptide

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The mRNA coding for the κ-type constant region (Cκ) was purified from two clones derived from the MPC-11 mouse myeloma. This mRNA directs the cell-free synthesis of a Cκ precursor (molecular weight, about 15,000) in which an extra piece, 17 residues long, precedes the NH2-terminal residue (Ala109) of the Cκ region. The partial sequence of the extra piece is: Met-X-Thr-Asp-Thr-Leu-Leu-Leu-Trp-Val-Leu-Leu-Leu-Trp-Val-Pro-X- (X is unknown). Met1 was shown to be the initiator methionine. The sequence of the Cκ extra piece is completely different from any known sequence preceding residue Ala109 in whole light (L) chains, thus establishing that the Cκ-region mRNA could not have originated from mRNA coding for the whole L chain. The structural features of the Cκ extra piece (marked hydrophobicity, size, and a methionine at the NH2-terminus) are identical to those characteristic of the NH2-terminal extra piece linked to the variable (V) region of whole L-chain precursors. In addition, the Cκ extra piece and the extra piece linked to the V region of MOPC-321 L chain have 70% sequence homology. These findings can be explained by the two genes-one Ig chain hypothesis, if we assume that the DNA coding for the extra piece (xp-DNA) is a constitutive part of the V gene. According to this model, the Cκ-region mRNA could have originated from: (i) translocation of this V gene to the C gene, deletion of the entire mature V gene, and “end-to-end” repair of the remaining xp-DNA to the C gene; (ii) translocation to the C gene only of the xp-DNA portion of the V gene. Alternatively, we may assume that the xp-DNA is not covalently linked to the mature V gene at all times, as might be the case for the DNA of hypervariable regions presumed to be in episomes. This raises the intriguing speculation that the xp-DNA represents a third distinct gene, designated xp-gene. The presumed xp-gene may be involved in the regulation of gene transcription: when linked to the mature V gene it initiates a chain of events leading to whole L-chain mRNA formation; when attached to the C gene it leads to its transcription to provide the C-region mRNA.

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