Structure of IL7 and the IL7 receptor

The cDNA of IL-7 (initially designated iympho-poietin 1) was first cloned from the murine stromal cell line IXN/A5. Subsequently, human IL-7 cDNA was cloned from the human hepatoma cell line SK-HEP-1. Murine IL-7 consists of 154 amino acid (aa) residues including a 25 aa signal peptide, whereas human IL-7 is 19 aa longer. This difference in size is due to the absence of an exon in the mouse gene, which corresponds to the 5th exon of the human II,-7 gene. Because of this deletion, murine IL-7 has two N-linked glycosylation sites in contrast to three in human IL-7. However, as deletion of these 19 aa from the human IL-7 molecule has no effect on its biological activity, this region is not essential. Except for this 19 aa region, human and mouse IL-7 are homologous and their overall homology in nucleotide sequence is 81% in the coding region. Both contain three intramolecular disulfide bridges. Although no significant sequence homology has been found with other cytokines, a structural model predicted from the amino acid sequence suggests that its tertiary structure is similar to that of IL-2, IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in that it has four a helices connected by long crossing loops.

Human IL-7Ra was cDNA cloned from a lung cancer cell line which bound recombinant IL-7, and the murine homolog was cloned from a pre-B leukemia cell line by using human IL-7 cDNA. Both encode 439 aa peptides and consist of extracellular, transmembrane and cytoplasmic regions. The presence of two fibronectin type III domains and a WSXWS motif indicates that this is a member of the cytokine receptor family. Although no domains with apparent enzymatic activity have been found in the cytoplasmic region, it shares a number of common motifs such as a box, acidic and serine-rich regions with other cytokine receptor family molecules. Evidence indicates that these regions play an important role for signaling through association with various other molecules. The homology between human and mouse IL-7Ra is about 60% at the amino acid sequence level, and human recombinant IL-7 is able to bind and stimulate the murine IL 7Ra.

While IL-7Ra alone can bind recombinant IL-7, it functions only in association with another cytokine receptor molecule, IL-2Ry (yc). Indeed, a monoclonal antibody against yc inhibited, though not completely, IL-7 binding to the receptor complex, suggesting a close association of the two molecules upon IL-7 stimulation.

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