Prosaposin

PSAP
Available structures PDB Ortholog search:PDBeRCSB List of PDB id codes 1M12,1N69,1SN6,2DOB,2GTG,2QYP,2R0R,2R1Q,2RB3,2Z9A,3BQP,3BQQ,4DDJ,4UEX,4V2O
Identifiers
Aliases	PSAP,GLBA, SAP1, prosaposin, SAP2, PSAPD, PARK24
External IDs	OMIM:176801;MGI:97783;HomoloGene:37680;GeneCards:PSAP;OMA:PSAP - orthologs
Gene location (Human) Chr. Chromosome 10 (human) Band 10q22.1 Start 71,816,298bp End 71,851,251bp
Gene location (Mouse) Chr. Chromosome 10 (mouse) Band 10 B4|10 30.02 cM Start 60,113,449bp End 60,138,376bp
RNA expressionpattern Bgee Human Mouse(ortholog) Top expressed in monocyte tendon of biceps brachii right adrenal cortex gallbladder internal globus pallidus stromal cell of endometrium Achilles tendon left adrenal gland visceral pleura left adrenal cortex Top expressed in stroma of bone marrow gastrula decidua vestibular membrane of cochlear duct choroid plexus of fourth ventricle dentate gyrus of hippocampal formation granule cell superior frontal gyrus cerebellar cortex mesenteric lymph nodes primary visual cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor binding protein binding lipid binding enzyme activator activity beta-galactosidase activity phospholipid binding protein homodimerization activity ganglioside GM1 binding ganglioside GM2 binding ganglioside GM3 binding ganglioside GT1b binding ganglioside GP1c binding identical protein binding protease binding Cellular component lysosomal membrane integral component of membrane mitochondrion lysosomal lumen extracellular exosome extracellular space lysosome plasma membrane azurophil granule membrane intracellular membrane-bounded organelle extracellular matrix extracellular region cytoplasm collagen-containing extracellular matrix late endosome Biological process lipid metabolism lipid transport epithelial cell differentiation involved in prostate gland development regulation of MAPK cascade glycosphingolipid metabolic process developmental growth adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway regulation of autophagy positive regulation of MAPK cascade cellular response to organic substance negative regulation of hydrogen peroxide-induced cell death regulation of lipid metabolic process prostate gland growth platelet degranulation sphingolipid metabolic process positive regulation of catalytic activity neutrophil degranulation ganglioside GM1 transport to membrane corneocyte development galactosylceramide catabolic process G protein-coupled receptor signaling pathway hearing myelination neuromuscular process controlling balance positive regulation of hydrolase activity urination cochlea development walking behavior cornified envelope assembly lysosomal transport Sources:Amigo/QuickGO
Orthologs Species Human Mouse Entrez 5660 19156 Ensembl ENSG00000197746 ENSMUSG00000004207 UniProt P07602 Q5BJH1 Q61207 RefSeq (mRNA) NM_002778 NM_001042465 NM_001042466 NM_001146120 NM_001146121 NM_001146122 NM_001146123 NM_001146124 NM_011179 RefSeq (protein) NP_001035930 NP_001035931 NP_002769 NP_002769.1 NP_001139592 NP_001139593 NP_001139594 NP_001139595 NP_001139596 NP_035309 Location (UCSC) Chr 10: 71.82 – 71.85 Mb Chr 10: 60.11 – 60.14 Mb PubMedsearch
Wikidata
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Prosaposin,also known asPSAP,is aproteinwhich in humans is encoded by thePSAPgene.

This highly conservedglycoproteinis a precursor for 4 cleavage products:saposinsA, B, C, and D. Saposin is an acronym forSphingolipidActivatorPrO[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 thelysosomalcompartment where they facilitate the catabolism ofglycosphingolipidswith shortoligosaccharidegroups. The precursor protein exists both as a secretory protein and as an integral membrane protein and hasneurotrophicactivities.

Saposins A–D are required for the hydrolysis of certain sphingolipids by specific lysosomal hydrolases.

Family members

• Saposin Awas 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,andgalactocerebroside.
• Saposin Bwas the first to be discovered and was found to be required as a heat-stable factor for hydrolysis ofsulfatidesbyarylsulfatase A.It is known by many different names, such as, sphingolipid activator protein-1 (SAP-1), sulfatide activator protein, GM₁ganglioside 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 Cwas the second saposin to be discovered and stimulates the hydrolysis of glycocerebroside by glycosylceramidase and galactocerebroside by galactosylceramidase.
• Saposin Dis 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. 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 solubledegradative enzymes.which contains fourSaposin-B domains,yielding the active saposins after proteolytic cleavage, and twoSaposin-A domainsthat 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 withGaucher disease,Tay–Sachs disease,andmetachromatic leukodystrophy.

See also

• Saposin protein domain

Further reading

• Gieselmann V, Zlotogora J, Harris A, et al. (1995)."Molecular genetics of metachromatic leukodystrophy".Hum. Mutat.4(4): 233–42.doi:10.1002/humu.1380040402.PMID7866401.S2CID23519007.
• 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.doi:10.1016/S0021-9258(19)50733-5.PMID1371116.
• Hiraiwa M, Soeda S, Kishimoto Y, O'Brien JS (1993)."Binding and transport of gangliosides by prosaposin".Proc. Natl. Acad. Sci. U.S.A.89(23): 11254–8.doi:10.1073/pnas.89.23.11254.PMC50528.PMID1454804.
• Rorman EG, Scheinker V, Grabowski GA (1992). "Structure and evolution of the human prosaposin chromosomal gene".Genomics.13(2): 312–8.doi:10.1016/0888-7543(92)90247-P.PMID1612590.
• Kondoh K, Hineno T, Sano A, Kakimoto Y (1992). "Isolation and characterization of prosaposin from human milk".Biochem. Biophys. Res. Commun.181(1): 286–92.doi:10.1016/S0006-291X(05)81415-9.PMID1958198.
• Holtschmidt H, Sandhoff K, Fürst W, et al. (1991)."The organization of the gene for the human cerebroside sulfate activator protein".FEBS Lett.280(2): 267–70.doi:10.1016/0014-5793(91)80308-P.PMID2013321.S2CID38952277.
• 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.doi:10.1016/S0021-9258(20)89483-6.PMID2019586.
• Hineno T, Sano A, Kondoh K, et al. (1991). "Secretion of sphingolipid hydrolase activator precursor, prosaposin".Biochem. Biophys. Res. Commun.176(2): 668–74.doi:10.1016/S0006-291X(05)80236-0.PMID2025281.
• 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.S2CID42681055.
• 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.S2CID23791396.
• 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.Bibcode:1990PNAS...87.2541K.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.doi:10.1093/oxfordjournals.jbchem.a122629.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".Genomics.5(3): 486–92.doi:10.1016/0888-7543(89)90014-1.PMID2515150.
• Morimoto S, Martin BM, Yamamoto Y, et al. (1989)."Saposin A: second cerebrosidase activator protein".Proc. Natl. Acad. Sci. U.S.A.86(9): 3389–93.Bibcode:1989PNAS...86.3389M.doi:10.1073/pnas.86.9.3389.PMC287138.PMID2717620.
• Dewji NN, Wenger DA, O'Brien JS (1988)."Nucleotide sequence of cloned cDNA for human sphingolipid activator protein 1 precursor".Proc. Natl. Acad. Sci. U.S.A.84(23): 8652–6.doi:10.1073/pnas.84.23.8652.PMC299604.PMID2825202.
• 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".Science.241(4869): 1098–101.Bibcode:1988Sci...241.1098O.doi:10.1126/science.2842863.PMID2842863.
• Morimoto S, Martin BM, Kishimoto Y, O'Brien JS (1988)."Saposin D: a sphingomyelinase activator".Biochem. Biophys. Res. Commun.156(1): 403–10.doi:10.1016/S0006-291X(88)80855-6.PMID2845979.
• Dewji N, Wenger D, Fujibayashi S, et al. (1986). "Molecular cloning of the sphingolipid activator protein-1 (SAP-1), the sulfatide sulfatase activator".Biochem. Biophys. Res. Commun.134(2): 989–94.doi:10.1016/S0006-291X(86)80518-6.PMID2868718.

External links

• Saposinsat the U.S. National Library of MedicineMedical Subject Headings(MeSH)