DP00733_C004: Saposin-CFASTA viewXML view

General information
DisProt:DP00733_C004
Name:Saposin-C
Synonym(s):SAP_HUMAN
A1 activator
Co-beta-glucosidase
Glucosylceramidase activator
Sphingolipid activator protein 2
SAP-2
Sap C or SapC or Sap-C
[cleavage product 4 of Proactivator polypeptide (S311-T391)]
First appeared in release:Release 6.01 (10/15/2012)
UniProt:P07602
UniGene: 
SwissProt: SAP_HUMAN
TrEMBL:  
NCBI (GI):  
Source organism:Homo sapiens (Human)
Sequence length:81
Percent disordered:72%
Homologues: 


Native sequence

        10         20         30         40         50         60
         |          |          |          |          |          |
SDVYCEVCEF LVKEVTKLID NNKTEKEILD AFDKMCSKLP KSLSEECQEV VDTYGSSILS - 60
ILLEEVSPEL VCSMLHLCSG T



Functional narrative    

DP00733_C004 is cleavage product 4 of Proactivator polypeptide, comprising aa S311-T391 of the parent protein.
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Function: 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).
SUBUNIT: Saposin-B is a homodimer.


Subcellular Location: Lysosome. Event=Alternative splicing; Named isoforms=3; Comment=Additional isoforms seem to exist; Name=Sap-mu-0; IsoId=P07602-1; Sequence=Displayed; Name=Sap-mu-6; IsoId=P07602-2; Sequence=VSP_006014; Name=Sap-mu-9; IsoId=P07602-3; Sequence=VSP_006015;
PTM: This precursor is proteolytically processed to 4 small peptides, which are similar to each other and are sphingolipid hydrolase activator proteins.
PTM: N-linked glycans show a high degree of microheterogeneity.
PTM: The one residue extended Saposin-B-Val is only found in 5% of the chains.
DISEASE: 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.
DISEASE: 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.
DISEASE: 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.
DISEASE: 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.
DISEASE: Note=Defects in PSAP saposin-D region are found in a variant of Tay-Sachs disease (GM2-gangliosidosis).
MISCELLANEOUS: Saposin-B co-purifies with 1 molecule of phosphatidylethanolamine.
SIMILARITY: Contains 2 saposin A-type domains.
SIMILARITY: Contains 4 saposin B-type domains.
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL='http://atlasgeneticsoncology.org/Genes/PSAPID42980ch10q22.html';
WEB RESOURCE: Name=GeneReviews; URL='http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PSAP';
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Region 1: 1-3 Region 2: 20-25 Region 3: 36-43 Region 4: 54-55 Region 7: 20-67 Region 5: 62-67 Region 6: 75-81

Map of ordered and disordered regions







Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.


Region 1
Type:Disordered
Name:N-terminal region
Location:1 - 3
Length:3
Region sequence:

SDV

Modification type: Native
PDB: 1M12:A, 1SN6:A
Structural/functional type: Function arises from the disordered state
Functional classes:  
Functional subclasses:  
Detection methods:
  1. Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; Saposin-C protein (PDB 1M12) 1 mM; KOH 0.1 M; NaCl (~10-20 mM) 10 mM; 90% H2O/10% D2O (or 100% D2O); U-15N (or U-15N, U-13C))

  2. Nuclear magnetic resonance (NMR) (298 K; pH: 6.4; Saposin-C protein (PDB 1SN6) 1 mM; Sodium dodecyl sulfate U-2H 25 mM; Sodium azide 0.01 %; 90% H2O/10% D2O (or 100% D2O); U-15N (or U-15N, U-13C); also at pH 6.8)
References:
  1. de Alba E, Weiler S, Tjandra N. "Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles." Biochemistry. 2003; 42(50): 14729-40. PubMed: 14674747

  2. Hawkins CA, de Alba E, Tjandra N. "Solution structure of human saposin C in a detergent environment." J. Mol. Biol.. 2005; 346(5): 1381-92. PubMed: 15713488
Comments:
PDB structure 1M12 is from de Alba et al (2003), PDB structure 1SN6 is from Hawkins et al (2004). Both NMR structures are in substantial agreement regarding disordered loops, with minor variations in the length of loops.


Region 2
Type:Disordered
Name:loop I-II
Location:20 - 25
Length:6
Region sequence:

DNNKTE

Modification type: Native
PDB: 1M12:A, 1SN6:A
Structural/functional type: Function arises from the disordered state
Functional classes: Modification site
Molecular recognition effectors
Functional subclasses: Protein-lipid interaction
Glycosylation
Detection methods:
  1. Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; Saposin-C protein (PDB 1M12) 1 mM; KOH 0.1 M; NaCl (~10-20 mM) 10 mM; 90% H2O/10% D2O (or 100% D2O); U-15N (or U-15N, U-13C))

  2. Nuclear magnetic resonance (NMR) (298 K; pH: 6.4; 90% H2O/10% D2O (or 100% D2O); also at pH 6.8; Saposin-C protein (PDB 1SN6) 1 mM; Sodium azide 0.01 %; Sodium dodecyl sulfate U-2H 25 mM; U-15N (or U-15N, U-13C))
References:
  1. de Alba E, Weiler S, Tjandra N. "Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles." Biochemistry. 2003; 42(50): 14729-40. PubMed: 14674747

  2. Hawkins CA, de Alba E, Tjandra N. "Solution structure of human saposin C in a detergent environment." J. Mol. Biol.. 2005; 346(5): 1381-92. PubMed: 15713488
Comments:
PDB structure 1M12 is from de Alba et al (2003), PDB structure 1SN6 is from Hawkins et al (2004). Both NMR structures are in substantial agreement regarding disordered loops, with minor variations in the length of loops.

Region 2 contains a glycosylation site at N22.


Region 3
Type:Disordered
Name:loop II-III
Location:36 - 43
Length:8
Region sequence:

CSKLPKSL

Modification type: Native
PDB: 1M12:A, 1SN6:A
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Protein-lipid interaction
Detection methods:
  1. Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O (or 100% D2O); KOH 0.1 M; NaCl (~10-20 mM) 10 mM; Saposin-C protein (PDB 1M12) 1 mM; U-15N (or U-15N, U-13C))

  2. Nuclear magnetic resonance (NMR) (298 K; pH: 6.4; 90% H2O/10% D2O (or 100% D2O); also at pH 6.8; Saposin-C protein (PDB 1SN6) 1 mM; Sodium azide 0.01 %; Sodium dodecyl sulfate U-2H 25 mM; U-15N (or U-15N, U-13C))
References:
  1. de Alba E, Weiler S, Tjandra N. "Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles." Biochemistry. 2003; 42(50): 14729-40. PubMed: 14674747

  2. Hawkins CA, de Alba E, Tjandra N. "Solution structure of human saposin C in a detergent environment." J. Mol. Biol.. 2005; 346(5): 1381-92. PubMed: 15713488
Comments:
PDB structure 1M12 is from de Alba et al (2003), PDB structure 1SN6 is from Hawkins et al (2004). Both NMR structures are in substantial agreement regarding disordered loops, with minor variations in the length of loops.


Region 4
Type:Disordered
Name:loop III-IV
Location:54 - 55
Length:2
Region sequence:

YG

Modification type: Native
PDB: 1M12:A, 1SN6:A
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Protein-lipid interaction
Detection methods:
  1. Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O (or 100% D2O); KOH 0.1 M; NaCl (~10-20 mM) 10 mM; Saposin-C protein (PDB 1M12) 1 mM; U-15N (or U-15N, U-13C))

  2. Nuclear magnetic resonance (NMR) (298 K; pH: 6.4; 90% H2O/10% D2O (or 100% D2O); also at pH 6.8; Saposin-C protein (PDB 1SN6) 1 mM; Sodium azide 0.01 %; Sodium dodecyl sulfate U-2H 25 mM; U-15N (or U-15N, U-13C))
References:
  1. de Alba E, Weiler S, Tjandra N. "Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles." Biochemistry. 2003; 42(50): 14729-40. PubMed: 14674747

  2. Hawkins CA, de Alba E, Tjandra N. "Solution structure of human saposin C in a detergent environment." J. Mol. Biol.. 2005; 346(5): 1381-92. PubMed: 15713488
Comments:
PDB structure 1M12 is from de Alba et al (2003), PDB structure 1SN6 is from Hawkins et al (2004). Both NMR structures are in substantial agreement regarding disordered loops, with minor variations in the length of loops.


Region 5
Type:Disordered
Name:loop IV-V
Location:62 - 67
Length:6
Region sequence:

LLEEVS

Modification type: Native
PDB: 1M12:A, 1SN6:A
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Protein-lipid interaction
Detection methods:
  1. Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O (or 100% D2O); KOH 0.1 M; NaCl (~10-20 mM) 10 mM; Saposin-C protein (PDB 1M12) 1 mM; U-15N (or U-15N, U-13C))

  2. Nuclear magnetic resonance (NMR) (298 K; pH: 6.4; 90% H2O/10% D2O (or 100% D2O); also at pH 6.8; Saposin-C protein (PDB 1SN6) 1 mM; Sodium azide 0.01 %; Sodium dodecyl sulfate U-2H 25 mM; U-15N (or U-15N, U-13C))
References:
  1. de Alba E, Weiler S, Tjandra N. "Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles." Biochemistry. 2003; 42(50): 14729-40. PubMed: 14674747

  2. Hawkins CA, de Alba E, Tjandra N. "Solution structure of human saposin C in a detergent environment." J. Mol. Biol.. 2005; 346(5): 1381-92. PubMed: 15713488
Comments:
PDB structure 1M12 is from de Alba et al (2003), PDB structure 1SN6 is from Hawkins et al (2004). Both NMR structures are in substantial agreement regarding disordered loops, with minor variations in the length of loops.


Region 6
Type:Disordered
Name:C-terminal region
Location:75 - 81
Length:7
Region sequence:

LHLCSGT

Modification type: Native
PDB: 1M12:A, 1SN6:A
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Protein-lipid interaction
Detection methods:
  1. Nuclear magnetic resonance (NMR) (298 K; pH: 6.8; 90% H2O/10% D2O (or 100% D2O); KOH 0.1 M; NaCl (~10-20 mM) 10 mM; Saposin-C protein (PDB 1M12) 1 mM; U-15N (or U-15N, U-13C))

  2. Nuclear magnetic resonance (NMR) (298 K; pH: 6.4; 90% H2O/10% D2O (or 100% D2O); also at pH 6.8; Saposin-C protein (PDB 1SN6) 1 mM; Sodium azide 0.01 %; Sodium dodecyl sulfate U-2H 25 mM; U-15N (or U-15N, U-13C))
References:
  1. de Alba E, Weiler S, Tjandra N. "Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles." Biochemistry. 2003; 42(50): 14729-40. PubMed: 14674747

  2. Hawkins CA, de Alba E, Tjandra N. "Solution structure of human saposin C in a detergent environment." J. Mol. Biol.. 2005; 346(5): 1381-92. PubMed: 15713488
Comments:
PDB structure 1M12 is from de Alba et al (2003), PDB structure 1SN6 is from Hawkins et al (2004). Both NMR structures are in substantial agreement regarding disordered loops, with minor variations in the length of loops.


Region 7
Type:Disordered
Name:flexible region
Location:20 - 67
Length:48
Region sequence:

DNNKTEKEILDAFDKMCSKLPKSLSEECQEVVDTYGSSILSILLEEVS

Modification type: Native
PDB: 1SN6:A, 2GTG:A, 2QYP:A, 2Z9A:A
Structural/functional type: Function arises via an order to disorder transition
Functional classes: Molecular recognition effectors
Functional subclasses: Protein-lipid interaction
Detection methods:
  1. Nuclear magnetic resonance (NMR) (298 K; pH: 6.4; 90% H2O/10% D2O (or 100% D2O); also at pH 6.8; Saposin-C protein (PDB 1SN6) 1 mM; Sodium azide 0.01 %; Sodium dodecyl sulfate U-2H 25 M; U-15N (or U-15N, U-13C))

  2. X-ray crystallography (298 K; pH: 6; Calcium chloride 0.4 M; PEG400 24 %; Saposin-C protein (PDB 2GTG); Sodium HEPES (pH 7.0) (or Sodium cacodylate (pH 6)) 0.1 M)

  3. X-ray crystallography (291 K; pH: 4; magnesium sulfate 240 mM; NaAcetate 20 mM; pentaerythriol ethoxylate 15/4 (v/v) 41 %; Saposin-C protein (PDB 2QYP and 2Z9A))
References:
  1. Ahn VE, Leyko P, Alattia JR, Chen L, Privé GG. "Crystal structures of saposins A and C." Protein Sci.. 2006; 15(8): 1849-57. PubMed: 16823039

  2. Hawkins CA, de Alba E, Tjandra N. "Solution structure of human saposin C in a detergent environment." J. Mol. Biol.. 2005; 346(5): 1381-92. PubMed: 15713488

  3. Rossmann M, Schultz-Heienbrok R, Behlke J, Remmel N, Alings C, Sandhoff K, Saenger W, Maier T. "Crystal structures of human saposins C andD: implications for lipid recognition and membrane interactions." Structure. 2008; 16(5): 809-17. PubMed: 18462685
Comments:
Region 7 encompasses several disordered loops as well as some helical structure.

According to Hawkins et al (2004), Region 7 exhibits substantially different conformations in the absence or presence of SDS. The presence of SDS causes Saposin-C to adopt an open conformation thus exposing the hydrophobic pocket. SDS was used to approximate the physiological membrane environment.
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Structure references for Region 7:
NMR structure: PDB 1SN6, Hawkins et al (2004).
X-ray crystal structures: PDB 2GTG, Ahn et al (2006); PDB 2QYP and 2Z9A, Rossman et al (2008).




Comments


AV sent 10/2/2012 (PMID 6823039)


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