PDBsum entry 1bci

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Hydrolase PDB id
Protein chain
123 a.a. *
_CA ×2
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: C2 domain of cytosolic phospholipase a2, nmr, minimized average structure
Structure: Cytosolic phospholipase a2. Chain: a. Fragment: c2 domain. Synonym: calb domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell_line: proprietary strain/gi400. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: proprietary strain/gi400.
NMR struc: 1 models
Authors: G.Y.Xu,T.Mcdonagh,H.A.Yu,E.A.Nalefski,J.D.Clark,D.A.Cumming
Key ref:
G.Y.Xu et al. (1998). Solution structure and membrane interactions of the C2 domain of cytosolic phospholipase A2. J Mol Biol, 280, 485-500. PubMed id: 9665851 DOI: 10.1006/jmbi.1998.1874
30-Apr-98     Release date:   25-Nov-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P47712  (PA24A_HUMAN) -  Cytosolic phospholipase A2
749 a.a.
123 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.  - Phospholipase A(2).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Phosphatidylcholine + H2O = 1-acylglycerophosphocholine + a carboxylate
+ H(2)O
= 1-acylglycerophosphocholine
+ carboxylate
      Cofactor: Ca(2+)
   Enzyme class 3: E.C.  - Lysophospholipase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 2-lysophosphatidylcholine + H2O = glycerophosphocholine + a carboxylate
+ H(2)O
= glycerophosphocholine
+ carboxylate
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site


DOI no: 10.1006/jmbi.1998.1874 J Mol Biol 280:485-500 (1998)
PubMed id: 9665851  
Solution structure and membrane interactions of the C2 domain of cytosolic phospholipase A2.
G.Y.Xu, T.McDonagh, H.A.Yu, E.A.Nalefski, J.D.Clark, D.A.Cumming.
The amino-terminal, 138 amino acid C2 domain of cytosolic phospholipase A2 (cPLA2-C2) mediates an initial step in the production of lipid mediators of inflammation: the Ca2+-dependent translocation of the enzyme to intracellular membranes with subsequent liberation of arachidonic acid. The high resolution solution structure of this Ca2+-dependent, lipid-binding domain (CaLB) has been determined using heteronuclear three-dimensional NMR spectroscopy. Secondary structure analysis, derived from several sets of spectroscopic data, shows that the domain is composed of eight antiparallel beta-strands with six interconnecting loops that fits the "type II" topology for C2 domains. Using a total of 2370 distance and torsional restraints, the structure was found to be a beta-sandwich in the "Greek key" motif. The solution structure of cPLA2-C2 domain is very similar to the X-ray crystal structure of the C2 domain of phospholipase-C-delta and phylogenetic analysis clarifies the structural role of highly conserved residues. Calorimetric studies further demonstrate that cPLA2-C2 binds two Ca2+ with observed Kds of approximately 2 microM in an entropically assisted process. Moreover, regions on cPLA2-C2 interacting with membranes were identified by 15N-HSQC-spectroscopy of cPLA2-C2 in the presence of low molecular weight lipid micelles. An extended binding site was identified that binds the phosphocholine headgroup in a Ca2+-dependent manner and also interacts with proximal regions of the membrane surface. Based upon these results, a structural model is presented for the mechanism of association of cPLA2 with its membrane substrate.
  Selected figure(s)  
Figure 3.
Figure 3. Summary of phylogenetic variance and tertiary structure features for human cPLA[2]-C2. The top line shows the numbered sequence of human cPLA[2]-C2 . The next line indicates residues absolutely conserved in cPLA[2] among species and the third line indicates residues conserved greater than 50% of the time in all C2 domains (indicates conservative substitution). Core residues, defined as those with solvent inaccessible hydrophobic side-chains, are indicated with filled triangles. Residues responsible for coordination of calcium ions are indicated with marked filled squares. Sheets, helices and calcium binding loops, as evident in the NMR-derived ensemble average structure, are represented as arrows, coils, or filled rectangles, respectively.
Figure 6.
Figure 6. Modeling glycerophosphocholine binding to cPLA[2]-C2. Docking of GPC to cPLA[2]-C2 was performed as described in Methods. Left: Modeled complex of GPC (licorice) bound to cPLA[2]-C2 with coordinated calcium ions colored light grey. Note F35 and M38 (CBL-1) just to the left of the quaternary amine of GPC with E100 (strand 6) center and just below. L39 (CBL-1) and Y96 (CBL-3) “cap” and partially obscure the bound ligand, with V97, and N95 (CBL-3) immediately to the right of GPC. The C-2 hydroxymethylene of glycerol can be observed just behind the L39 and Y96 “cap”. Interactions with the ligand resemble those of annexin-V bound to glycerophosphoethanolamine [Swairjo et al 1995]. Right: Protein “cartoon” of the GPC-cPLA[2]-C2 complex. The orientation and view of the complex is identical to that on the left. This Figure was generated with VMD and RAYSHADE.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1998, 280, 485-500) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20023071 H.Moreno, A.S.Linford, C.A.Gilchrist, and W.A.Petri (2010).
Phospholipid-binding protein EhC2A mediates calcium-dependent translocation of transcription factor URE3-BP to the plasma membrane of Entamoeba histolytica.
  Eukaryot Cell, 9, 695-704.  
19632983 A.Radhakrishnan, A.Stein, R.Jahn, and D.Fasshauer (2009).
The Ca2+ affinity of synaptotagmin 1 is markedly increased by a specific interaction of its C2B domain with phosphatidylinositol 4,5-bisphosphate.
  J Biol Chem, 284, 25749-25760.  
19917234 C.H.Chen, S.Málková, S.V.Pingali, F.Long, S.Garde, W.Cho, and M.L.Schlossman (2009).
Configuration of PKCalpha-C2 domain bound to mixed SOPC/SOPS lipid monolayers.
  Biophys J, 97, 2794-2802.  
19176526 D.E.Tucker, M.Ghosh, F.Ghomashchi, R.Loper, S.Suram, B.S.John, M.Girotti, J.G.Bollinger, M.H.Gelb, and C.C.Leslie (2009).
Role of phosphorylation and basic residues in the catalytic domain of cytosolic phospholipase A2alpha in regulating interfacial kinetics and binding and cellular function.
  J Biol Chem, 284, 9596-9611.  
18280495 E.Johnson, L.Bruschweiler-Li, S.A.Showalter, G.W.Vuister, F.Zhang, and R.Brüschweiler (2008).
Structure and dynamics of Ca2+-binding domain 1 of the Na+/Ca2+ exchanger in the presence and in the absence of Ca2+.
  J Mol Biol, 377, 945-955.  
17890395 F.Dancea, K.Kami, and M.Overduin (2008).
Lipid interaction networks of peripheral membrane proteins revealed by data-driven micelle docking.
  Biophys J, 94, 515-524.  
18211893 Y.H.Hsu, J.E.Burke, D.L.Stephens, R.A.Deems, S.Li, K.M.Asmus, V.L.Woods, and E.A.Dennis (2008).
Calcium binding rigidifies the C2 domain and the intradomain interaction of GIVA phospholipase A2 as revealed by hydrogen/deuterium exchange mass spectrometry.
  J Biol Chem, 283, 9820-9827.  
17367165 J.A.Corbin, J.H.Evans, K.E.Landgraf, and J.J.Falke (2007).
Mechanism of specific membrane targeting by C2 domains: localized pools of target lipids enhance Ca2+ affinity.
  Biochemistry, 46, 4322-4336.  
17510957 J.L.Jiménez, and B.Davletov (2007).
Beta-strand recombination in tricalbin evolution and the origin of synaptotagmin-like C2 domains.
  Proteins, 68, 770-778.  
17071664 S.Jaud, D.J.Tobias, J.J.Falke, and S.H.White (2007).
Self-induced docking site of a deeply embedded peripheral membrane protein.
  Biophys J, 92, 517-524.  
17085504 S.Varma, and E.Jakobsson (2007).
The cPLA2 C2alpha domain in solution: structure and dynamics of its Ca2+-activated and cation-free states.
  Biophys J, 92, 966-976.  
16200410 B.Z.Guo, G.Xu, Y.G.Cao, C.C.Holbrook, and R.E.Lynch (2006).
Identification and characterization of phospholipase D and its association with drought susceptibilities in peanut (Arachis hypogaea).
  Planta, 223, 512-520.  
16617059 M.Ghosh, R.Loper, M.H.Gelb, and C.C.Leslie (2006).
Identification of the expressed form of human cytosolic phospholipase A2beta (cPLA2beta): cPLA2beta3 is a novel variant localized to mitochondria and early endosomes.
  J Biol Chem, 281, 16615-16624.  
16510840 M.N.Diouf, K.Sayasith, R.Lefebvre, D.W.Silversides, J.Sirois, and J.G.Lussier (2006).
Expression of phospholipase A2 group IVA (PLA2G4A) is upregulated by human chorionic gonadotropin in bovine granulosa cells of ovulatory follicles.
  Biol Reprod, 74, 1096-1103.  
15994899 S.Málková, F.Long, R.V.Stahelin, S.V.Pingali, D.Murray, W.Cho, and M.L.Schlossman (2005).
X-ray reflectivity studies of cPLA2{alpha}-C2 domains adsorbed onto Langmuir monolayers of SOPC.
  Biophys J, 89, 1861-1873.  
15866882 T.Ohto, N.Uozumi, T.Hirabayashi, and T.Shimizu (2005).
Identification of novel cytosolic phospholipase A(2)s, murine cPLA(2){delta}, {epsilon}, and {zeta}, which form a gene cluster with cPLA(2){beta}.
  J Biol Chem, 280, 24576-24583.  
14676210 B.J.Pettus, A.Bielawska, P.Subramanian, D.S.Wijesinghe, M.Maceyka, C.C.Leslie, J.H.Evans, J.Freiberg, P.Roddy, Y.A.Hannun, and C.E.Chalfant (2004).
Ceramide 1-phosphate is a direct activator of cytosolic phospholipase A2.
  J Biol Chem, 279, 11320-11326.  
14623879 J.H.Evans, and C.C.Leslie (2004).
The cytosolic phospholipase A2 catalytic domain modulates association and residence time at Golgi membranes.
  J Biol Chem, 279, 6005-6016.  
13679516 J.H.Evans, S.H.Gerber, D.Murray, and C.C.Leslie (2004).
The calcium binding loops of the cytosolic phospholipase A2 C2 domain specify targeting to Golgi and ER in live cells.
  Mol Biol Cell, 15, 371-383.  
15007075 N.M.Okeley, and M.H.Gelb (2004).
A designed probe for acidic phospholipids reveals the unique enriched anionic character of the cytosolic face of the mammalian plasma membrane.
  J Biol Chem, 279, 21833-21840.  
15305015 T.Hirabayashi, T.Murayama, and T.Shimizu (2004).
Regulatory mechanism and physiological role of cytosolic phospholipase A2.
  Biol Pharm Bull, 27, 1168-1173.  
12663792 L.Balakireva, G.Schoehn, E.Thouvenin, and J.Chroboczek (2003).
Binding of adenovirus capsid to dipalmitoyl phosphatidylcholine provides a novel pathway for virus entry.
  J Virol, 77, 4858-4866.  
12531893 R.V.Stahelin, J.D.Rafter, S.Das, and W.Cho (2003).
The molecular basis of differential subcellular localization of C2 domains of protein kinase C-alpha and group IVa cytosolic phospholipase A2.
  J Biol Chem, 278, 12452-12460.  
12676927 W.K.Han, A.Sapirstein, C.C.Hung, A.Alessandrini, and J.V.Bonventre (2003).
Cross-talk between cytosolic phospholipase A2 alpha (cPLA2 alpha) and secretory phospholipase A2 (sPLA2) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells: sPLA2 regulates cPLA2 alpha activity that is responsible for arachidonic acid release.
  J Biol Chem, 278, 24153-24163.  
12009889 A.A.Frazier, M.A.Wisner, N.J.Malmberg, K.G.Victor, G.E.Fanucci, E.A.Nalefski, J.J.Falke, and D.S.Cafiso (2002).
Membrane orientation and position of the C2 domain from cPLA2 by site-directed spin labeling.
  Biochemistry, 41, 6282-6292.  
12370087 J.H.Evans, D.J.Fergus, and C.C.Leslie (2002).
Inhibition of the MEK1/ERK pathway reduces arachidonic acid release independently of cPLA2 phosphorylation and translocation.
  BMC Biochem, 3, 30.  
11258923 E.A.Nalefski, M.A.Wisner, J.Z.Chen, S.R.Sprang, M.Fukuda, K.Mikoshiba, and J.J.Falke (2001).
C2 domains from different Ca2+ signaling pathways display functional and mechanistic diversity.
  Biochemistry, 40, 3089-3100.  
10673441 A.Dessen (2000).
Phospholipase A(2) enzymes: structural diversity in lipid messenger metabolism.
  Structure, 8, R15-R22.  
10634937 A.G.Buckland, and D.C.Wilton (2000).
Anionic phospholipids, interfacial binding and the regulation of cell functions.
  Biochim Biophys Acta, 1483, 199-216.  
10672019 C.May, M.Höhne, P.Gnau, K.Schwennesen, and H.Kindl (2000).
The N-terminal beta-barrel structure of lipid body lipoxygenase mediates its binding to liposomes and lipid bodies.
  Eur J Biochem, 267, 1100-1109.  
10940243 J.H.Hurley, and S.Misra (2000).
Signaling and subcellular targeting by membrane-binding domains.
  Annu Rev Biophys Biomol Struct, 29, 49-79.  
10828354 M.A.Gijón, D.M.Spencer, and C.C.Leslie (2000).
Recent advances in the regulation of cytosolic phospholipase A(2).
  Adv Enzyme Regul, 40, 255-268.  
10811903 R.A.García, C.E.Forde, and H.A.Godwin (2000).
Calcium triggers an intramolecular association of the C2 domains in synaptotagmin.
  Proc Natl Acad Sci U S A, 97, 5883-5888.  
11080682 T.Hirabayashi, and T.Shimizu (2000).
Localization and regulation of cytosolic phospholipase A(2).
  Biochim Biophys Acta, 1488, 124-138.  
10359764 A.Ball, R.Nielsen, M.H.Gelb, and B.H.Robinson (1999).
Interfacial membrane docking of cytosolic phospholipase A2 C2 domain using electrostatic potential-modulated spin relaxation magnetic resonance.
  Proc Natl Acad Sci U S A, 96, 6637-6642.  
10319815 A.Dessen, J.Tang, H.Schmidt, M.Stahl, J.D.Clark, J.Seehra, and W.S.Somers (1999).
Crystal structure of human cytosolic phospholipase A2 reveals a novel topology and catalytic mechanism.
  Cell, 97, 349-360.
PDB code: 1cjy
10092653 L.Bittova, M.Sumandea, and W.Cho (1999).
A structure-function study of the C2 domain of cytosolic phospholipase A2. Identification of essential calcium ligands and hydrophobic membrane binding residues.
  J Biol Chem, 274, 9665-9672.  
10366595 M.A.Gijón, D.M.Spencer, A.L.Kaiser, and C.C.Leslie (1999).
Role of phosphorylation sites and the C2 domain in regulation of cytosolic phospholipase A2.
  J Cell Biol, 145, 1219-1232.  
10329700 O.Perisic, H.F.Paterson, G.Mosedale, S.Lara-González, and R.L.Williams (1999).
Mapping the phospholipid-binding surface and translocation determinants of the C2 domain from cytosolic phospholipase A2.
  J Biol Chem, 274, 14979-14987.  
10601489 Y.Takahashi, H.Kawajiri, T.Yoshimoto, N.Hoshi, and H.Higashida (1999).
12-Lipoxygenase overexpression in rodent NG108-15 cells enhances membrane excitability by inhibiting M-type K+ channels.
  J Physiol, 521, 567-574.  
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.