Prosaposin

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Prosaposin
Protein PSAP PDB 1m12.png
PDB rendering based on 1m12.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PSAP ; GLBA; SAP1
External IDs OMIM176801 MGI97783 HomoloGene37680 GeneCards: PSAP Gene
RNA expression pattern
PBB GE PSAP 200866 s at tn.png
PBB GE PSAP 200871 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5660 19156
Ensembl ENSG00000197746 ENSMUSG00000004207
UniProt P07602 Q61207
RefSeq (mRNA) NM_001042465 NM_001146120
RefSeq (protein) NP_001035930 NP_001139592
Location (UCSC) Chr 10:
73.58 – 73.61 Mb
Chr 10:
60.28 – 60.3 Mb
PubMed search [1] [2]

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]

See also[edit]

References[edit]

  1. ^ a b "Entrez Gene: PSAP prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)". 
  2. ^ 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. 
  3. ^ 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. 
  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. 
  5. ^ 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. 
  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. 
  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. 
  8. ^ 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. 
  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. 
  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. 

Further reading[edit]

External links[edit]