Protein and gene structure

cDNAs for CD59 have been isolated by several independent groups. The nucleotide sequence encodes a precursor polypeptide of 128 amino acids in length, the first 25 residues constituting a signal peptide. The sequence contains one site for N-linked glycosylation at Asnl8, and the carbohydrate attached here is a common biantennary structure accounting for approximately 25% of the molecular weight of CD59. At the C-terminus there is a hydrophobic stretch of residues characteristic of proteins which are processed to carry a GPI anchor. The presence of such an anchor in the case of CD59 was originally confirmed by release of the protein from various cell surfaces by phosphatidylinositol-specific phospho-lipase C. Subsequently, protein sequencing of tryptic fragments and nuclear magnetic resonance (NMR) studies of the protein purified from human urine have indicated that the GPI anchor is attached to Asn77. The protein contains a total of 10 cysteine residues which form disulfide bonds as follows: Cys3-26, Cys6-13, Cysl9-39, Cys45-63, Cvs64-69.

CD59 is unique in the complement control protein superfamily in that it bears no structural or immunologic relationship with other member proteins, although these are distinctly related to one another and encoded by genes which are situated together in the RCA (regulators of complement activation) region on chromosome 1. The gene for CD59 is in contrast located on the short arm of chromosome 11, distributed throughout over 27 kb of genomic DNA. Although initial studies identified four exons, a fifth alternately spliced exon has recently been discovered between what were originally considered to be exons 1 and 2. The transcriptional start site for both forms of mRNA is the same. Since the newly identified exon occurs within the 5' untranslated region of the CD59 transcript there is still no evidence as yet to suggest that there are alternative forms of the mature protein. Both types of transcript are expressed con-cordantly in all the cell types analyzed so far, and their expression appears to be regulated similarly. The purpose of the alternately spliced exon is therefore not known.

The structure of the CD59 gene is similar to that of the murine Ly-6 antigens and of the human urokinase plasminogen activator receptor (HUPAR). These and other proteins such as the mouse thymocyte and B cell antigen ThB, and the squid glycoprotein SGP2, constitute a separate family of proteins which share some sequence homology (in particular, conserved cysteine residues) and therefore some structural similarity. CD59 has on occasion been proposed as the human homolog of the murine Ly-6 antigens, despite only 25% sequence identity between the two, and differences in the pattern and regulation of gene expression. However, the recent cloning of mouse CD59 clearly demonstrates that CD59 and Ly-6 are distinct proteins.

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