Prosaposin

PDB rendering based on 1m12.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1M12, 1N69, 1SN6, 2DOB, 2GTG, 2QYP, 2R0R, 2R1Q, 2RB3, 2Z9A, 3BQP, 3BQQ, 4DDJ

Identifiers

Symbols

PSAP ; GLBA; SAP1

External IDs

OMIM: 176801 MGI: 97783 HomoloGene: 37680 GeneCards: PSAP Gene

Gene ontology
Molecular function	• G-protein coupled receptor binding • protein binding • enzyme activator activity • lipid binding
Cellular component	• extracellular region • extracellular space • nucleoplasm • nucleolus • mitochondrion • lysosomal membrane • Golgi apparatus • integral component of membrane • lysosomal lumen • intracellular membrane-bounded organelle • extracellular exosome
Biological process	• platelet degranulation • sphingolipid metabolic process • glycosphingolipid metabolic process • lipid transport • adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway • blood coagulation • regulation of lipid metabolic process • platelet activation • positive regulation of catalytic activity • positive regulation of MAPK cascade • small molecule metabolic process • prostate gland growth • epithelial cell differentiation involved in prostate gland development • cellular response to organic substance • negative regulation of hydrogen peroxide-induced cell death
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 10:
71.82 – 71.85 Mb

Chr 10:
60.28 – 60.3 Mb

PubMed search

Prosaposin, also known as PSAP, is a protein which in humans is encoded by the PSAP gene.^[1]

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.^[2] 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.^[1]

Saposins A-D are required for the hydrolysis of certain sphingolipids by specific lysosomal hydrolases.^[3]

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-methlyumbelliferyl-β-glucoside, glucocerebroside, and galactocerebroside.^[4]

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.^[5] 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.^[3]

Crystal structures of human saposins A-D

Saposin A (PDB: 2DOB).^[6]

Saposin B (PDB: 1N69).^[7]

Saposin C dimer in an open conformation (PDB: 2QYP).^[8]

Saposin D (PDB: 2RB3).^[8]

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).^[3] 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.^[3] 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.^[5]

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.^[9]^[10]

Clinical significance

Mutations in this gene have been associated with Gaucher disease, Tay-Sachs disease, and metachromatic leukodystrophy.^[2]

References

1 2 "Entrez Gene: PSAP prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)".
1 2 Morimoto S, Yamamoto Y, O'Brien JS, Kishimoto Y (May 1990). "Distribution of saposin proteins (sphingolipid activator proteins) in lysosomal storage and other diseases". Proc. Natl. Acad. Sci. U.S.A. 87 (9): 3493–7. doi:10.1073/pnas.87.9.3493. PMC 53927. PMID 2110365.
1 2 3 4 Kishimoto Y, Hiraiwa M, O'Brien JS (September 1992). "Saposins: structure, function, distribution, and molecular genetics". J. Lipid Res. 33 (9): 1255–67. PMID 1402395.
↑ Morimoto S, Martin BM, Yamamoto Y, Kretz KA, O'Brien JS, Kishimoto Y (May 1989). "Saposin A: second cerebrosidase activator protein". Proc. Natl. Acad. Sci. U.S.A. 86 (9): 3389–93. doi:10.1073/pnas.86.9.3389. PMC 287138. PMID 2717620.
1 2 O'Brien JS, Kishimoto Y (March 1991). "Saposin proteins: structure, function, and role in human lysosomal storage disorders". FASEB J. 5 (3): 301–8. PMID 2001789.
↑ Ahn VE, Leyko P, Alattia JR, Chen L, Privé GG (August 2006). "Crystal structures of saposins A and C". Protein Sci. 15 (8): 1849–57. doi:10.1110/ps.062256606. PMC 2242594. PMID 16823039.
↑ 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. PMC 140876. PMID 12518053.
1 2 Rossmann 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". Structure 16 (5): 809–17. doi:10.1016/j.str.2008.02.016. PMID 18462685.
↑ Ponting CP (1994). "Acid sphingomyelinase possesses a domain homologous to its activator proteins: saposins B and D". Protein Sci. 3 (2): 359–361. doi:10.1002/pro.5560030219. PMC 2142785. PMID 8003971.
↑ Hofmann K, Tschopp J (1996). "Cytotoxic T cells: more weapons for new targets?". Trends Microbiol. 4 (3): 91–94. doi:10.1016/0966-842X(96)81522-8. PMID 8868085.

External links

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

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