CD45 contains a large extracellular domain, a single transmembrane region, and two cytoplasmic PTPase domains (Figure 1). cDNAs have been isolated from human, rat, mouse, chicken and shark and comparison of the predicted protein sequences indicates a conservation of domain structure. The extracellular domain of CD45 consists of three distinguishable regions: an O-linked carbohydrate domain, a cyst-eine-containing domain and a domain containing three fibronectin type III repeats (which also contain several cysteines). Electron microscopy analysis of the extracellular domain demonstrates that the O-linked carbohydrate region which is most membrane distal has an extended rod conformation. Multiple isoforms of CD45 exist, ranging in molecular weight from 180 to 220 kDa. The basis for the different isoforms is alternative splicing of exons that encode part of the O-linked carbohydrate region. Since this region has an extended conformation, the length of the extracellular domain is dramatically altered (28 nm for the low molecular weight isoform and 51 nm for the high molecular weight isoform) (Figure 2). The O-linked carbohydrate region is encoded by exons 3-8. cDNA cloning shows that exons 4, 5 and 6 (also named A, B and C) are spliced in a variety of combinations to give rise to eight distinct protein products. In addition, a ninth isoform is predicted to exist that is the product of a splice between exons 3 and 8. The proposed nomenclature for the different CD45 isoforms is shown in Table 1.

The extracellular domain contains numerous sites for N-linked carbohydrate addition. Indeed, CD45 is 25% carbohydrate by weight. Owing to the high level of expression on lymphocytes, 100000 molecules per cell, and its large size, CD45 occupies approximately 10% of the lymphocyte cell surface and bears much of the carbohydrate of these cells. Further diversification of CD45 species is generated with the addition of carbohydrate groups by cell type-specific and developmentally regulated glycosyl-transferases. The existence of specific modifications on CD45 has been demonstrated using monoclonal antibodies that recognize distinct carbohydrate groups.

The cytoplasmic domain of CD45 contains two tandemly arranged tyrosine phosphatase domains. Mutational analysis suggests the first, membrane proximal, domain is both necessary and sufficient for biological responses and contains most if not all the catalytic activity. This is consistent with the observation that the sequence of the second domain contains changes at critical amino acids in the active site signature motif 'HCSAGXGRTG'. Nonetheless, it is possible that the second domain does possess intrinsic phosphatase activity. Alternatively, the second domain may function to regulate substrate availability.

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