prosaposin

Prosaposin
	PDB rendering based on 1m12.
Available structures
PDB	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
	v; t; e;

プロサ・シン

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/16 13:59:09」(JST)

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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

^ ^a ^b "Entrez Gene: PSAP prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)".
^ ^a ^b 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.
^ ^a ^b ^c ^d 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.
^ ^a ^b 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.
^ ^a ^b 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)

UpToDate Contents

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1. 異染性白質ジストロフィー metachromatic leukodystrophy
2. ゴーシェ病：病因、臨床症状、および診断 gaucher disease pathogenesis clinical manifestations and diagnosis

English Journal

Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes.

Kalinina N1, Kharlampieva D2, Loguinova M3, Butenko I4, Pobeguts O5, Efimenko A6, Ageeva L7, Sharonov G8, Ischenko D9, Alekseev D10, Grigorieva O11, Sysoeva V12, Rubina K13, Lazarev V14, Govorun V15.
Stem cell research & therapy.Stem Cell Res Ther.2015 Nov 11;6:221. doi: 10.1186/s13287-015-0209-8.
INTRODUCTION: This study was aimed at deciphering the secretome of adipose-derived mesenchymal stromal cells (ADSCs) cultured in standard and hypoxic conditions to reveal proteins, which may be responsible for regenerative action of these cells.METHODS: Human ADSCs were isolated from 10 healthy dono
PMID 26560317

Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells.

Ambrosi G1, Ghezzi C1, Zangaglia R1, Levandis G1, Pacchetti C1, Blandini F2.
Neurobiology of disease.Neurobiol Dis.2015 Oct;82:235-42. doi: 10.1016/j.nbd.2015.06.008. Epub 2015 Jun 19.
Heterozygous mutations in GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are a major risk factor for sporadic Parkinson's disease (PD). Defective GCase has been reported in fibroblasts of GBA1-mutant PD patients and pharmacological chaperone ambroxol has been shown to correct s
PMID 26094596

Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.

Zhou X1, Sun L2, Bastos de Oliveira F1, Qi X3, Brown WJ4, Smolka MB1, Sun Y5, Hu F6.
The Journal of cell biology.J Cell Biol.2015 Sep 14;210(6):991-1002. doi: 10.1083/jcb.201502029.
Mutations in the progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests a critical role of PGRN in lysosomes. However, how PGRN is trafficked to lysosomes i
PMID 26370502

Japanese Journal

酸化ストレス時におけるProsaposinのアポトーシスシグナル制御機構

古田麻衣子
福岡大学薬学集報 10(0), 153-154, 2010-02
NAID 110007522482

Regional expression of prosaposin in the wild-type and saposin D-deficient mouse brain detected by an anti-mouse prosaposin-specific antibody

YONESHIGE Azusa,SUZUKI Kunihiko,KOJIMA Naoya,MATSUDA Junko
Proceedings of the Japan Academy, Series B 85(9), 422-434, 2009
… Prosaposin is a precursor of saposins A, B, C, and D. … The notion that prosaposin itself is likely involved in brain development led us to generate an anti-mouse prosaposin-specific antibody that do not cross-react with any of the processed saposins. … We have used it to study expression of prosaposin in the brain of wild-type (WT) and saposin D knockout mice (Sap-D-/-). …
NAID 130000137985

Related Pictures

[entrez-1] "Entrez Gene: PSAP prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)".

[pmid2110365-2] 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.

[pmid1402395-3] 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.

[pmid2717620-4] 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.

[pmid2001789-5] 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.

[pmid16823039-6] 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.

[pmid12518053-7] 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.

[pmid18462685-8] 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.

[PUB00005721-9] 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.

[PUB00005765-10] 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.

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