PDBsum entry 1m12

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protein links
Membrane protein PDB id
Protein chain
84 a.a. *
* Residue conservation analysis
PDB id:
Name: Membrane protein
Title: Nmr solution structure of human saposin c
Structure: Saposin c. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 20 models
Authors: E.De Alba,S.Weiler,N.Tjandra
Key ref: Alba et al. (2003). Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles. Biochemistry, 42, 14729-14740. PubMed id: 14674747 DOI: 10.1021/bi0301338
17-Jun-02     Release date:   29-Jul-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P07602  (SAP_HUMAN) -  Prosaposin
524 a.a.
84 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     lysosome   1 term 
  Biological process     lipid metabolic process   2 terms 


DOI no: 10.1021/bi0301338 Biochemistry 42:14729-14740 (2003)
PubMed id: 14674747  
Solution structure of human saposin C: pH-dependent interaction with phospholipid vesicles. Alba, S.Weiler, N.Tjandra.
Saposin C binds to membranes to activate lipid degradation in lysosomes. To get insights into saposin C's function, we have determined its three-dimensional structure by NMR and investigated its interaction with phospholipid vesicles. Saposin C adopts the saposin-fold common to other members of the family. In contrast, the electrostatic surface revealed by the NMR structure is remarkably different. We suggest that charge distribution in the protein surface can modulate membrane interaction leading to the functional diversity of this family. We find that the binding of saposin C to phospholipid vesicles is a pH-controlled reversible process. The pH dependence of this interaction is sigmoidal, with an apparent pK(a) for binding close to 5.3. The pK(a) values of many solvent-exposed Glu residues are anomalously high and close to the binding pK(a). Our NMR data are consistent with the absence of a conformational change prior to membrane binding. All this information suggests that the negatively charged electrostatic surface of saposin C needs to be partially neutralized to trigger membrane binding. We have studied the membrane-binding behavior of a mutant of saposin C designed to decrease the negative charge of the electrostatic surface. The results support our conclusion on the importance of protein surface neutralization in binding. Since saposin C is a lysosomal protein and pH gradients occur in lysosomes, we propose that lipid degradation in the lysosome could be switched on and off by saposin C's reversible binding to membranes.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19298372 M.R.Beck, G.T.Dekoster, D.P.Cistola, and W.E.Goldman (2009).
NMR structure of a fungal virulence factor reveals structural homology with mammalian saposin B.
  Mol Microbiol, 72, 344-353.
PDB code: 2jv7
19521672 M.R.Landon, R.L.Lieberman, Q.Q.Hoang, S.Ju, J.M.Caaveiro, S.D.Orwig, D.Kozakov, R.Brenke, G.Y.Chuang, D.Beglov, S.Vajda, G.A.Petsko, and D.Ringe (2009).
Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.
  J Comput Aided Mol Des, 23, 491-500.  
19374450 R.L.Lieberman, J.A.D'aquino, D.Ringe, and G.A.Petsko (2009).
Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability.
  Biochemistry, 48, 4816-4827.
PDB codes: 3gxd 3gxf 3gxi 3gxm 3gxn 3gxp 3gxt
18453694 K.Popovic, and G.G.Privé (2008).
Structures of the human ceramide activator protein saposin D.
  Acta Crystallogr D Biol Crystallogr, 64, 589-594.
PDB codes: 3bqp 3bqq
18462685 M.Rossmann, R.Schultz-Heienbrok, J.Behlke, N.Remmel, C.Alings, K.Sandhoff, W.Saenger, and T.Maier (2008).
Crystal structures of human saposins C andD: implications for lipid recognition and membrane interactions.
  Structure, 16, 809-817.
PDB codes: 2qyp 2r0r 2r1q 2rb3 2z9a
17803231 S.Atrian, E.López-Viñas, P.Gómez-Puertas, A.Chabás, L.Vilageliu, and D.Grinberg (2008).
An evolutionary and structure-based docking model for glucocerebrosidase-saposin C and glucocerebrosidase-substrate interactions - relevance for Gaucher disease.
  Proteins, 70, 882-891.  
18783340 Y.Kacher, B.Brumshtein, S.Boldin-Adamsky, L.Toker, A.Shainskaya, I.Silman, J.L.Sussman, and A.H.Futerman (2008).
Acid beta-glucosidase: insights from structural analysis and relevance to Gaucher disease therapy.
  Biol Chem, 389, 1361-1369.
PDB code: 2vt0
18037897 D.C.Barral, and M.B.Brenner (2007).
CD1 antigen presentation: how it works.
  Nat Rev Immunol, 7, 929-941.  
17565495 G.Da Costa, L.Mouret, S.Chevance, E.Le Rumeur, and A.Bondon (2007).
NMR of molecules interacting with lipids in small unilamellar vesicles.
  Eur Biophys J, 36, 933-942.  
17235497 J.Furrer, M.John, H.Kessler, and B.Luy (2007).
J-Spectroscopy in the presence of residual dipolar couplings: determination of one-bond coupling constants and scalable resolution.
  J Biomol NMR, 37, 231-243.  
17954913 J.R.Alattia, J.E.Shaw, C.M.Yip, and G.G.Privé (2007).
Molecular imaging of membrane interfaces reveals mode of beta-glucosidase activation by saposin C.
  Proc Natl Acad Sci U S A, 104, 17394-17399.  
17704143 S.Abu-Baker, X.Qi, and G.A.Lorigan (2007).
Investigating the interaction of saposin C with POPS and POPC phospholipids: a solid-state NMR spectroscopic study.
  Biophys J, 93, 3480-3490.  
16445682 J.E.Gumperz (2006).
The ins and outs of CD1 molecules: bringing lipids under immunological surveillance.
  Traffic, 7, 2.  
  16511279 R.Schultz-Heienbrok, N.Remmel, R.Klingenstein, M.Rossocha, K.Sandhoff, W.Saenger, and T.Maier (2006).
Crystallization and preliminary characterization of three different crystal forms of human saposin C heterologously expressed in Pichia pastoris.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 117-120.  
16823039 V.E.Ahn, P.Leyko, J.R.Alattia, L.Chen, and G.G.Privé (2006).
Crystal structures of saposins A and C.
  Protein Sci, 15, 1849-1857.
PDB codes: 2dob 2gtg
16316452 A.J.Waring, F.J.Walther, L.M.Gordon, J.M.Hernandez-Juviel, T.Hong, M.A.Sherman, C.Alonso, T.Alig, A.Braun, D.Bacon, and J.A.Zasadzinski (2005).
The role of charged amphipathic helices in the structure and function of surfactant protein B.
  J Pept Res, 66, 364-374.
PDB code: 1ssz
15901739 M.L.Malakhova, L.Malinina, H.M.Pike, A.T.Kanack, D.J.Patel, and R.E.Brown (2005).
Point mutational analysis of the liganding site in human glycolipid transfer protein. Functionality of the complex.
  J Biol Chem, 280, 26312-26320.  
16230343 T.Kolter, F.Winau, U.E.Schaible, M.Leippe, and K.Sandhoff (2005).
Lipid-binding proteins in membrane digestion, antigen presentation, and antimicrobial defense.
  J Biol Chem, 280, 41125-41128.  
16212488 T.Kolter, and K.Sandhoff (2005).
Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids.
  Annu Rev Cell Dev Biol, 21, 81.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.