Prosaposin also known as PSAP is a protein which in humans is encoded by the PSAPgene.
This highly conserved glycoprotein is a precursor for 4 cleavage products: saposins A, B, C, and D. Saposin is an acronym for Sphingolipid Activator PrO[S]teINs. Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities.
Saposins A-D are required for the hydrolysis of certain sphingolipids by specific lysosomal hydrolases.
Saposin A was identified as an N-terminal domain in the prosaposin cDNA prior to its isolation. It is known to stimulate the enzymatic hydrolysis of 4-methlyumbelliferyl-β-glucoside, glucocerebroside, and galactocerebroside.
Saposin B was the first to be discovered and was found to be required as a heat-stable factor for hydrolysis of sulfatides by arylsulfatase A. It is known by many different names, such as, sphingolipid activator protein-1 (SAP-1), sulfatide activator protein, GM1 ganglioside activator, dispersin, and nonspecific. It has been observed that this particular saposin activates many enzymes through interaction with the substrates not the enzymes themselves.
Saposin C was the second saposin to be discovered and stimulates the hydrolysis of glycocerebroside by glycosylceramidase and galactocerebroside by galactoslyceramidase.
Saposin D is not well known to due lack of investigation at this point in time. It was predicted from the cDNA sequence of prosaposin, like saposin A. Ezymatic stimulation is very specific for this particular glycoprotein and it not understood completely.
Every saposin contains about 80 amino acid residues and has six equally placed cytesines, two prolines, and a glycosylation site (two in saposin A, one each in saposins B, C, and D). Since saposins characteristics of extreme heat-stability, adundance of disulfide linkages, and resistance to most proteases, they are assumed to be extremely compact and rigidly disulfide-linked molecules. Each saposin has an α-helical structure that is seen as being important for stimulation because this structure is maximal at a pH of 4.5; which is optimal for many lysosomal hydrolases. This helical structure is seen in all (especially with the first region), but saposin has been predicted to have β-sheet configuration due to it first 24 amino acids of the N-end.
They probably act by isolating the lipid substrate from the membrane surroundings, thus making it more accessible to the soluble degradative enzymes. which contains four Saposin-B domains, yielding the active saposins after proteolytic cleavage, and two Saposin-A domains that are removed in the activation reaction. The Saposin-B domains also occur in other proteins, many of them active in the lysis of membranes.
^Ahn VE, Faull KF, Whitelegge JP, Fluharty AL, Privé GG (January 2003). "Crystal structure of saposin B reveals a dimeric shell for lipid binding". Proc. Natl. Acad. Sci. U.S.A.100 (1): 38–43. doi:10.1073/pnas.0136947100. PMC140876. PMID12518053.
^ abRossmann M, Schultz-Heienbrok R, Behlke J, Remmel N, Alings C, Sandhoff K, Saenger W, Maier T (May 2008). "Crystal structures of human saposins C and D: implications for lipid recognition and membrane interactions". Structure16 (5): 809–17. doi:10.1016/j.str.2008.02.016. PMID18462685.
Schnabel D, Schröder M, Fürst W, et al. (1992). "Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene". J. Biol. Chem.267 (5): 3312–5. PMID1371116.
Holtschmidt H, Sandhoff K, Kwon HY, et al. (1991). "Sulfatide activator protein. Alternative splicing that generates three mRNAs and a newly found mutation responsible for a clinical disease". J. Biol. Chem.266 (12): 7556–60. PMID2019586.
Schnabel D, Schröder M, Sandhoff K (1991). "Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease". FEBS Lett.284 (1): 57–9. doi:10.1016/0014-5793(91)80760-Z. PMID2060627.
Zhang XL, Rafi MA, DeGala G, Wenger DA (1991). "The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy". Hum. Genet.87 (2): 211–5. doi:10.1007/BF00204185. PMID2066109.
Fürst W, Schubert J, Machleidt W, et al. (1990). "The complete amino-acid sequences of human ganglioside GM2 activator protein and cerebroside sulfate activator protein". Eur. J. Biochem.192 (3): 709–14. doi:10.1111/j.1432-1033.1990.tb19280.x. PMID2209618.
Rafi MA, Zhang XL, DeGala G, Wenger DA (1990). "Detection of a point mutation in sphingolipid activator protein-1 mRNA in patients with a variant form of metachromatic leukodystrophy". Biochem. Biophys. Res. Commun.166 (2): 1017–23. doi:10.1016/0006-291X(90)90912-7. PMID2302219.
Kretz KA, Carson GS, Morimoto S, et al. (1990). "Characterization of a mutation in a family with saposin B deficiency: a glycosylation site defect". Proc. Natl. Acad. Sci. U.S.A.87 (7): 2541–4. doi:10.1073/pnas.87.7.2541. PMC53725. PMID2320574.
Nakano T, Sandhoff K, Stümper J, et al. (1989). "Structure of full-length cDNA coding for sulfatide activator, a Co-beta-glucosidase and two other homologous proteins: two alternate forms of the sulfatide activator". J. Biochem.105 (2): 152–4. PMID2498298.
Rorman EG, Grabowski GA (1990). "Molecular cloning of a human co-beta-glucosidase cDNA: evidence that four sphingolipid hydrolase activator proteins are encoded by single genes in humans and rats". Genomics5 (3): 486–92. doi:10.1016/0888-7543(89)90014-1. PMID2515150.
O'Brien JS, Kretz KA, Dewji N, et al. (1988). "Coding of two sphingolipid activator proteins (SAP-1 and SAP-2) by same genetic locus". Science241 (4869): 1098–101. doi:10.1126/science.2842863. PMID2842863.