Biology:Prosaposin

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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-methylumbelliferyl-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 galactosylceramidase.
  • 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. Enzymatic stimulation is very specific for this particular glycoprotein and it not understood completely.[3]
  • GM2A (GM2 ganglioside activator) has been viewed as a member of the SAP family and has been called SAP-3 (sphingolipid activator protein 3)[6]
Crystal structures of human saposins A-D

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, 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.[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.[10][11]

Clinical significance

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

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: PSAP prosaposin (variant Gaucher disease and variant metachromatic leukodystrophy)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5660. 
  2. ↑ 2.0 2.1 "Distribution of saposin proteins (sphingolipid activator proteins) in lysosomal storage and other diseases". Proc. Natl. Acad. Sci. U.S.A. 87 (9): 3493–7. May 1990. doi:10.1073/pnas.87.9.3493. PMID 2110365. Bibcode: 1990PNAS...87.3493M. 
  3. ↑ 3.0 3.1 3.2 3.3 "Saposins: structure, function, distribution, and molecular genetics". J. Lipid Res. 33 (9): 1255–67. September 1992. doi:10.1016/S0022-2275(20)40540-1. PMID 1402395. http://www.jlr.org/cgi/content/abstract/33/9/1255. 
  4. ↑ "Saposin A: second cerebrosidase activator protein". Proc. Natl. Acad. Sci. U.S.A. 86 (9): 3389–93. May 1989. doi:10.1073/pnas.86.9.3389. PMID 2717620. Bibcode: 1989PNAS...86.3389M. 
  5. ↑ 5.0 5.1 "Saposin proteins: structure, function, and role in human lysosomal storage disorders". FASEB J. 5 (3): 301–8. March 1991. doi:10.1096/fasebj.5.3.2001789. PMID 2001789. http://www.fasebj.org/cgi/pmidlookup?view=long&pmid=2001789. 
  6. ↑ HUGO Gene Nomenclature Committee, "GM2A", HGNC database, https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:4367, retrieved 2016-03-13. 
  7. ↑ "Crystal structures of saposins A and C". Protein Sci. 15 (8): 1849–57. August 2006. doi:10.1110/ps.062256606. PMID 16823039. 
  8. ↑ "Crystal structure of saposin B reveals a dimeric shell for lipid binding". Proc. Natl. Acad. Sci. U.S.A. 100 (1): 38–43. January 2003. doi:10.1073/pnas.0136947100. PMID 12518053. Bibcode: 2003PNAS..100...38A. 
  9. ↑ 9.0 9.1 "Crystal structures of human saposins C and D: implications for lipid recognition and membrane interactions". Structure 16 (5): 809–17. May 2008. doi:10.1016/j.str.2008.02.016. PMID 18462685. 
  10. ↑ 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. PMID 8003971. 
  11. ↑ "Cytotoxic T cells: more weapons for new targets?". Trends Microbiol. 4 (3): 91–94. 1996. doi:10.1016/0966-842X(96)81522-8. PMID 8868085. 

Further reading

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Prosaposin&oldid=3683462"