Golgi phosphoprotein 2 in physiology and in diseases

The 73？kDa protein is coded by the gene GOLM1 located on human chromosome 9q21.33 (mouse chromosome 13) and was originally cloned by differential screening of a cDNA library derived from liver tissue of a patient with adult giant-cell hepatitis [1], a rare form of hepatitis with suspected viral etiology. GOLPH2 was also independently identified in “the secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins using a biological signal sequence trap in yeast cells aided by computational tools [2]. The gene is conserved in chimpanzee, dog, cow, mouse, chicken, and zebrafish. The closest human homologue to GOLPH2 is the cancer susceptibility candidate gene 4 (CASC4) protein (Swiss-Prot Q6P4E1), a single-pass type II membrane protein that co-localizes with GOLPH2 (unpublished data of the authors), the increased expression level of which is associated with HER-2/neu proto-oncogene overexpression [3].GOLPH2 genomic sequence predicts 11 exons and two splicing variants. The transcript variant 1 (NM_016548.3) is 3100nt in length and contains exons 2 to 11, while transcript variant 2 (NM_177937.2) is 3092nt in length and contains exons 1, and 3 to 11. Both variants encode the same open reading frame. The biological significance of these variants is not clear.Sequence analysis reveals that GOLPH2 contains a predicted transmembrane domain (TMD) at the N-terminal region, consistent with the observation that the protein can be found in the serum or cell culture supernatant, likely by secretion or by a shedding mechanism. Strikingly, it appears that the protein is entirely helical after the TMD, with two predicted continuous helical regions of 150 to 200 residues in length (Figure 1A). This striking helical nature of the protein may explain its observed resistance to proteases (unpublished data of the authors), because proteolysis requires a stretch of extended conformation such as β-strand conformation or random