9i63 | pdb_00009i63

Synthetic Human Saposin D glycoprotein

Structural highlights

9i63 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.65Å
Ligands:	NLE, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SAP_HUMAN Defects in PSAP are the cause of combined saposin deficiency (CSAPD) [MIM:611721; also known as prosaposin deficiency. CSAPD is due to absence of all saposins, leading to a fatal storage disorder with hepatosplenomegaly and severe neurological involvement.^[1] ^[2] Defects in PSAP saposin-B region are the cause of leukodystrophy metachromatic due to saposin-B deficiency (MLD-SAPB) [MIM:249900. MLD-SAPB is an atypical form of metachromatic leukodystrophy. It is characterized by tissue accumulation of cerebroside-3-sulfate, demyelination, periventricular white matter abnormalities, peripheral neuropathy. Additional neurological features include dysarthria, ataxic gait, psychomotr regression, seizures, cognitive decline and spastic quadriparesis. Defects in PSAP saposin-C region are the cause of atypical Gaucher disease (AGD) [MIM:610539. Affected individuals have marked glucosylceramide accumulation in the spleen without having a deficiency of glucosylceramide-beta glucosidase characteristic of classic Gaucher disease, a lysosomal storage disorder.^[3] ^[4] Defects in PSAP saposin-A region are the cause of atypical Krabbe disease (AKRD) [MIM:611722. AKRD is a disorder of galactosylceramide metabolism. AKRD features include progressive encephalopathy and abnormal myelination in the cerebral white matter resembling Krabbe disease.^[5] Note=Defects in PSAP saposin-D region are found in a variant of Tay-Sachs disease (GM2-gangliosidosis).

Function

SAP_HUMAN The lysosomal degradation of sphingolipids takes place by the sequential action of specific hydrolases. Some of these enzymes require specific low-molecular mass, non-enzymic proteins: the sphingolipids activator proteins (coproteins). Saposin-A and saposin-C stimulate the hydrolysis of glucosylceramide by beta-glucosylceramidase (EC 3.2.1.45) and galactosylceramide by beta-galactosylceramidase (EC 3.2.1.46). Saposin-C apparently acts by combining with the enzyme and acidic lipid to form an activated complex, rather than by solubilizing the substrate. Saposin-B stimulates the hydrolysis of galacto-cerebroside sulfate by arylsulfatase A (EC 3.1.6.8), GM1 gangliosides by beta-galactosidase (EC 3.2.1.23) and globotriaosylceramide by alpha-galactosidase A (EC 3.2.1.22). Saposin-B forms a solubilizing complex with the substrates of the sphingolipid hydrolases. Saposin-D is a specific sphingomyelin phosphodiesterase activator (EC 3.1.4.12).

Publication Abstract from PubMed

The main glycoforms of the hydrophobic lysosomal glycoprotein saposin D (SapD) were synthesized by native chemical ligation. An approach for the challenging solid-phase synthesis of the fragments was developed. Three SapD glycoforms were obtained following a general and robust refolding and purification protocol. A crystal structure of one glycoform confirmed its native structure and disulfide pattern. Functional assays revealed that the lipid-binding properties of three SapD glycoforms are highly affected by the single sugar moiety of SapD showing a dependency of the size and the type of N-glycan.

Synthetic Glycoforms Reveal Carbohydrate-Dependent Bioactivity of Human Saposin D.,Graf CGF, Schulz C, Schmalzlein M, Heinlein C, Monnich M, Perkams L, Puttner M, Boos I, Hessefort M, Lombana Sanchez JN, Weyand M, Steegborn C, Breiden B, Ross K, Schwarzmann G, Sandhoff K, Unverzagt C Angew Chem Int Ed Engl. 2017 May 2;56(19):5252-5257. doi: 10.1002/anie.201701362. , Epub 2017 Apr 5. PMID:28378443^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Schnabel D, Schroder M, Furst W, Klein A, Hurwitz R, Zenk T, Weber J, Harzer K, Paton BC, Poulos A, et al.. 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. 1992 Feb 15;267(5):3312-5. PMID:1371116
↑ Hulkova H, Cervenkova M, Ledvinova J, Tochackova M, Hrebicek M, Poupetova H, Befekadu A, Berna L, Paton BC, Harzer K, Boor A, Smid F, Elleder M. A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hum Mol Genet. 2001 Apr 15;10(9):927-40. PMID:11309366
↑ Schnabel D, Schroder M, Sandhoff K. Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease. FEBS Lett. 1991 Jun 17;284(1):57-9. PMID:2060627
↑ Tylki-Szymanska A, Czartoryska B, Vanier MT, Poorthuis BJ, Groener JA, Lugowska A, Millat G, Vaccaro AM, Jurkiewicz E. Non-neuronopathic Gaucher disease due to saposin C deficiency. Clin Genet. 2007 Dec;72(6):538-42. Epub 2007 Oct 7. PMID:17919309 doi:https://dx.doi.org/10.1111/j.1399-0004.2007.00899.x
↑ Spiegel R, Bach G, Sury V, Mengistu G, Meidan B, Shalev S, Shneor Y, Mandel H, Zeigler M. A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol Genet Metab. 2005 Feb;84(2):160-6. PMID:15773042
↑ Graf CGF, Schulz C, Schmälzlein M, Heinlein C, Mönnich M, Perkams L, Püttner M, Boos I, Hessefort M, Lombana Sanchez JN, Weyand M, Steegborn C, Breiden B, Ross K, Schwarzmann G, Sandhoff K, Unverzagt C. Synthetic Glycoforms Reveal Carbohydrate-Dependent Bioactivity of Human Saposin D. Angew Chem Int Ed Engl. 2017 May 2;56(19):5252-5257. PMID:28378443 doi:10.1002/anie.201701362

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OCA

[1] Schnabel D, Schroder M, Furst W, Klein A, Hurwitz R, Zenk T, Weber J, Harzer K, Paton BC, Poulos A, et al.. 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. 1992 Feb 15;267(5):3312-5. PMID:1371116

[2] Hulkova H, Cervenkova M, Ledvinova J, Tochackova M, Hrebicek M, Poupetova H, Befekadu A, Berna L, Paton BC, Harzer K, Boor A, Smid F, Elleder M. A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation. Hum Mol Genet. 2001 Apr 15;10(9):927-40. PMID:11309366

[3] Schnabel D, Schroder M, Sandhoff K. Mutation in the sphingolipid activator protein 2 in a patient with a variant of Gaucher disease. FEBS Lett. 1991 Jun 17;284(1):57-9. PMID:2060627

[4] Tylki-Szymanska A, Czartoryska B, Vanier MT, Poorthuis BJ, Groener JA, Lugowska A, Millat G, Vaccaro AM, Jurkiewicz E. Non-neuronopathic Gaucher disease due to saposin C deficiency. Clin Genet. 2007 Dec;72(6):538-42. Epub 2007 Oct 7. PMID:17919309 doi:https://dx.doi.org/10.1111/j.1399-0004.2007.00899.x

[5] Spiegel R, Bach G, Sury V, Mengistu G, Meidan B, Shalev S, Shneor Y, Mandel H, Zeigler M. A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol Genet Metab. 2005 Feb;84(2):160-6. PMID:15773042

[6] Graf CGF, Schulz C, Schmälzlein M, Heinlein C, Mönnich M, Perkams L, Püttner M, Boos I, Hessefort M, Lombana Sanchez JN, Weyand M, Steegborn C, Breiden B, Ross K, Schwarzmann G, Sandhoff K, Unverzagt C. Synthetic Glycoforms Reveal Carbohydrate-Dependent Bioactivity of Human Saposin D. Angew Chem Int Ed Engl. 2017 May 2;56(19):5252-5257. PMID:28378443 doi:10.1002/anie.201701362

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9i63 | pdb_00009i63

Synthetic Human Saposin D glycoprotein

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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