Biology:Prosaposin

Prosaposin, also known as PSAP, is a protein which in humans is encoded by the PSAP gene.

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.

Family members

• 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-methylumbelliferyl-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 galactosylceramidase.
• Saposin D is not well known due to a lack of investigation at this point in time. It was predicted from the cDNA sequence of prosaposin, like saposin A. Enzymatic stimulation is very specific for this particular glycoprotein and it not understood completely.
• GM2A (GM2 ganglioside activator) has been viewed as a member of the SAP family and has been called SAP-3 (sphingolipid activator protein 3)

Crystal structures of human saposins A-D

• 
  Saposin A (PDB: 2DOB​).
• 
  Saposin B (PDB: 1N69​).
• 
  Saposin C dimer in an open conformation (PDB: 2QYP​).
• 
  Saposin D (PDB: 2RB3​).

Structure

Every saposin contains about 80 amino acid residues and has six equally placed cysteines, 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, abundance 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.

Function

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.

Clinical significance

Mutations in this gene have been associated with Gaucher disease, Tay–Sachs disease,Metachromatic leukodystrophy and Combined Saposin Deficiency.

See also

• Saposin protein domain

Further reading

• "Molecular genetics of metachromatic leukodystrophy". Human Mutation 4 (4): 233–242. 1994. doi:10.1002/humu.1380040402. PMID 7866401. 
• "Simultaneous deficiency of sphingolipid activator proteins 1 and 2 is caused by a mutation in the initiation codon of their common gene". The Journal of Biological Chemistry 267 (5): 3312–3315. February 1992. doi:10.1016/S0021-9258(19)50733-5. PMID 1371116. 
• "Binding and transport of gangliosides by prosaposin". Proceedings of the National Academy of Sciences of the United States of America 89 (23): 11254–11258. 1993. doi:10.1073/pnas.89.23.11254. PMID 1454804. 
• "Structure and evolution of the human prosaposin chromosomal gene". Genomics 13 (2): 312–318. 1992. doi:10.1016/0888-7543(92)90247-P. PMID 1612590. 
• "Isolation and characterization of prosaposin from human milk". Biochemical and Biophysical Research Communications 181 (1): 286–292. 1992. doi:10.1016/S0006-291X(05)81415-9. PMID 1958198. 
• "The organization of the gene for the human cerebroside sulfate activator protein". FEBS Letters 280 (2): 267–270. March 1991. doi:10.1016/0014-5793(91)80308-P. PMID 2013321. 
• "Sulfatide activator protein. Alternative splicing that generates three mRNAs and a newly found mutation responsible for a clinical disease". The Journal of Biological Chemistry 266 (12): 7556–7560. April 1991. doi:10.1016/S0021-9258(20)89483-6. PMID 2019586. 
• "Secretion of sphingolipid hydrolase activator precursor, prosaposin". Biochemical and Biophysical Research Communications 176 (2): 668–674. April 1991. doi:10.1016/S0006-291X(05)80236-0. PMID 2025281. 
• "Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease". FEBS Letters 284 (1): 57–59. 1991. doi:10.1016/0014-5793(91)80760-Z. PMID 2060627. 
• "The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy". Human Genetics 87 (2): 211–215. 1991. doi:10.1007/BF00204185. PMID 2066109. 
• "The complete amino-acid sequences of human ganglioside GM2 activator protein and cerebroside sulfate activator protein". European Journal of Biochemistry 192 (3): 709–714. September 1990. doi:10.1111/j.1432-1033.1990.tb19280.x. PMID 2209618. 
• "Detection of a point mutation in sphingolipid activator protein-1 mRNA in patients with a variant form of metachromatic leukodystrophy". Biochemical and Biophysical Research Communications 166 (2): 1017–1023. 1990. doi:10.1016/0006-291X(90)90912-7. PMID 2302219. 
• "Characterization of a mutation in a family with saposin B deficiency: a glycosylation site defect". Proceedings of the National Academy of Sciences of the United States of America 87 (7): 2541–2544. April 1990. doi:10.1073/pnas.87.7.2541. PMID 2320574. Bibcode: 1990PNAS...87.2541K. 
• "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". Journal of Biochemistry 105 (2): 152–154. February 1989. doi:10.1093/oxfordjournals.jbchem.a122629. PMID 2498298. 
• "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". Genomics 5 (3): 486–492. 1990. doi:10.1016/0888-7543(89)90014-1. PMID 2515150. 
• "Nucleotide sequence of cloned cDNA for human sphingolipid activator protein 1 precursor". Proceedings of the National Academy of Sciences of the United States of America 84 (23): 8652–8656. 1988. doi:10.1073/pnas.84.23.8652. PMID 2825202. 
• "Coding of two sphingolipid activator proteins (SAP-1 and SAP-2) by same genetic locus". Science (New York, N.Y.) 241 (4869): 1098–1101. August 1988. doi:10.1126/science.2842863. PMID 2842863. Bibcode: 1988Sci...241.1098O. 
• "Saposin D: a sphingomyelinase activator". Biochemical and Biophysical Research Communications 156 (1): 403–410. 1988. doi:10.1016/S0006-291X(88)80855-6. PMID 2845979. 
• "Molecular cloning of the sphingolipid activator protein-1 (SAP-1), the sulfatide sulfatase activator". Biochemical and Biophysical Research Communications 134 (2): 989–994. January 1986. doi:10.1016/S0006-291X(86)80518-6. PMID 2868718. 

External links

• Saposins at the US National Library of Medicine Medical Subject Headings (MeSH)