Saposins and their precursor, prosaposin: Multifunctional glycoproteins

Sphingolipids are ubiquitous components of animal plasma membranes and are especially rich in nervous system. They are assumed to be present at the outer leaflet of the membrane and to be involved in a variety of biological phenomena as key molecules. Although their definitive functions remain unclear, the various aspects of their metabolism are now well defined. In mammalian cells, sphingolipids are degradated in lysosome by the sequential action of acid hydrolases. Deficiency of even one of these hydrolases causes tissue accumulation of sphingolipid and results in severe neuronal disorders, sphingolipidoses. During the past three decades, it was shown that some of the sphingolipid hydrolases require the assistance of small heat-stable nonenzymatic proteins, sphingolipid activator proteins. Four such proteins, named saposins A to D, are known. They are glycoproteins with molecular weights of 12-15 kDa and show highly homologous sequence identities to each other. Importantly, all six cysteine residues in each molecule, an N-glycosylation site, and proline residues affecting turn structures are conserved at nearly identical positions. All of the cysteine residues are involved in formation of disulfide bonds. They make the structures of the saposins compact and extraordinarily stable. The resulting molecular configurations provide amphiphilic character. All four saposins are coded as separate domains in a single precursor protein, prosaposin. In this review, we describe biogenesis and function of saposins as not only the activators for sphingolipid hydrolysis but also as transporters of these lipids. In addition, we review history of the saposins, present knowledge of their functions, and prospective saposin research. We also review the recently discovered function of prosapsoin as a neurotrophic factor.