Posttranslational Processing of Human alpha2-HS Glycoprotein (Human Fetuin). Evidence for the Production of a Phosphorylated Single-Chain Form by Hepatoma Cells

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Abstract
Alpha 2-HS glycoprotein (alpha 2-HS) is a major protein occurring in human blood and calciferous tissues. Due to extensive sequence identity, alpha 2-HS has been grouped with the fetuins, a family of proteins that occur in fetal plasma in high concentrations. Native alpha 2-HS undergoes a series of posttranslational modifications including proteolytic processing, multiple N-glycosylations and O-glycosylations, and sulfation of the carbohydrate side chains. Various two-chain forms of alpha 2-HS have been prepared from human plasma, however, the single-chain precursor has not yet been isolated. Here, we have studied the biosynthesis of alpha 2-HS by a human hepatoma cell line, HepG2. We demonstrate that a single-chain form and the two-chain form of alpha 2-HS are secreted by this cell line. The alpha 2-HS forms are further modified by phosphorylation on multiple serine residues. Mapping studies indicate that the connecting peptide region releasable from the heavy chain of alpha 2-HS contains at least one such phosphorylation site. Our results identify proteolytic trimming and/or phosphorylation as modifications possibly regulating the biological effects of alpha 2-HS and the homologous fetuins.