スフィンゴ脂質活性化タンパク質

WordNet

any of a large group of nitrogenous organic compounds that are essential constituents of living cells; consist of polymers of amino acids; essential in the diet of animals for growth and for repair of tissues; can be obtained from meat and eggs and milk and legumes; "a diet high in protein"
(biology) any agency bringing about activation; a molecule that increases the activity of an enzyme or a protein that increases the production of a gene product in DNA transcription

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/04 12:01:46」(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[edit]

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[edit]

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).^[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[edit]

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[edit]

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

References[edit]

^ ^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[edit]

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

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English Journal

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Adada MM1, Canals D1, Jeong N1, Kelkar AD1, Hernandez-Corbacho M1, Pulkoski-Gross MJ1, Donaldson JC1, Hannun YA1, Obeid LM2.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology.FASEB J.2015 Nov;29(11):4654-69. doi: 10.1096/fj.15-274340. Epub 2015 Jul 24.
The bioactive sphingolipid sphingosine-1-phosphate (S1P) mediates cellular proliferation, mitogenesis, inflammation, and angiogenesis. These biologies are mediated through S1P binding to specific GPCRs [sphingosine-1-phosphate receptor (S1PR)1-5] and some other less well-characterized intracellular
PMID 26209696

Caveolin-1 regulates osteoclast differentiation by suppressing cFms degradation.

Lee YD1, Yoon SH1, Ji E2, Kim HH1.
Experimental & molecular medicine.Exp Mol Med.2015 Oct 30;47:e192. doi: 10.1038/emm.2015.77.
Caveolae are flask-shaped cell-surface membranes, which consist of cholesterol, sphingolipids and caveolin proteins. In a microarray analysis, we found that caveolin-1 (Cav-1) was upregulated by receptor activator of NFκB ligand (RANKL), the osteoclast differentiation factor. Silencing of Cav-1 inh
PMID 26514084

The relevance of the storage of subunit c of ATP synthase in different forms and models of Batten disease (NCLs).

Palmer DN1.
Biochimica et biophysica acta.Biochim Biophys Acta.2015 Oct;1852(10 Pt B):2287-91. doi: 10.1016/j.bbadis.2015.06.014. Epub 2015 Jun 17.
The discoveries of specific protein storage in the NCLs, particularly of subunit c of ATP synthase in most, and the sphingolipid activator proteins, SAPs or saposins A and D in CLN1, CLN10 and an unassigned form are reviewed. The subunit c stored in the relevant NCLs is the complete mature molecule
PMID 26093153

Japanese Journal

Aglycon of Rhizochalin from the Rhizochalina incrustata Induces Apoptosis via Activation of AMP-Activated Protein Kinase in HT-29 Colon Cancer Cells

Khanal Prem,Kang Bong Seok,Yun Hyo Jeong [他],Cho Hae-Guk,Makarieva Tatyana Nikolaevna,Choi Hong Seok
Biological and Pharmaceutical Bulletin 34(10), 1553-1558, 2011
… Rhizochalin is a two-headed sphingolipid-like compound isolated from the sponge Rhizochalina incrustata. … Here, we demonstrate that aglycon of rhizochalin (AglRhz) from the Rhizochalina incrustata induces AMP-activated protein kinase (AMPK) phosphorylation, and thereby inhibits mammalian target of rapamycin (mTOR)-p70S6 kinase-extracellular signal-regulated kinase (ERK) signaling and activator protein 1 (AP-1) activity via phosphorylation of Raptor in HT-29 cells. …
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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 [他],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. Saposins are indispensable for lysosomal hydrolysis of sphingolipids. The notion that prosaposin itself is likely involved in brain development le …
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Mutation in saposin D domain of sphingolipid activator protein gene causes urinary system defects and cerebellar Purkinje cell degeneration with accumulation of hydroxy fatty acid-containing ceramide in mouse

Matsuda J,Kido M,Tadano-Aritomi K,Ishizuka I,Tominaga K,Toida K,Takeda E,Suzuki K,Kuroda Y
HUMAN MOLECULAR GENETICS 13(21), 2709-2723, 2004
NAID 120004371725

「SAP1 deficiency」

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	• enzyme activator activity; • lipid binding;
Cellular component	• extracellular region; • extracellular space; • mitochondrion; • lysosomal membrane; • Golgi apparatus; • integral to membrane; • lysosomal lumen; • intracellular membrane-bounded organelle;
Biological process	• platelet degranulation; • sphingolipid metabolic process; • glycosphingolipid metabolic process; • lipid transport; • blood coagulation; • regulation of lipid metabolic process; • platelet activation; • positive regulation of catalytic activity; • regulation of MAPK cascade; • small molecule metabolic process; • prostate gland growth; • epithelial cell differentiation involved in prostate gland development; • cellular response to organic substance;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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