PDBsum entry 1hzf

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protein links
Immune system PDB id
Protein chain
302 a.a. *
Waters ×77
* Residue conservation analysis
PDB id:
Name: Immune system
Title: C4adg fragment of human complement factor c4a
Structure: Complement factor c4a. Chain: a. Fragment: c4adg. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: c4hu. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
2.30Å     R-factor:   0.215     R-free:   0.233
Authors: J.M.H.Van Den Elsen,A.Martin,V.Wong,L.Clemenza,D.R.Rose, D.E.Isenman
Key ref:
J.M.van den Elsen et al. (2002). X-ray crystal structure of the C4d fragment of human complement component C4. J Mol Biol, 322, 1103-1115. PubMed id: 12367531 DOI: 10.1016/S0022-2836(02)00854-9
24-Jan-01     Release date:   09-Oct-02    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P0C0L4  (CO4A_HUMAN) -  Complement C4-A
1744 a.a.
302 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   1 term 


DOI no: 10.1016/S0022-2836(02)00854-9 J Mol Biol 322:1103-1115 (2002)
PubMed id: 12367531  
X-ray crystal structure of the C4d fragment of human complement component C4.
J.M.van den Elsen, A.Martin, V.Wong, L.Clemenza, D.R.Rose, D.E.Isenman.
C4 fulfills a vital role in the propagation of the classical and lectin pathways of the complement system. Although there are no reports to date of a C4 functional activity that is mediated solely by the C4d region, evidence clearly points to it having a vital role in a number of the properties of native C4 and its major activation fragment, C4b. Contained within the C4d region are the thioester-forming residues, the four isotype-specific residues controlling the C4A/C4B transacylation preferences, a binding site for nascent C3b important in assembling the classical pathway C5 convertase and determinants for the Chido/Rodgers (Ch/Rg) blood group antigens. In view of its functional importance, we undertook to determine the three-dimensional structure of C4d by X-ray crystallography. Here we report the 2.3A resolution structure of C4Ad, the C4d fragment derived from the human C4A isotype. Although the approximately 30% sequence identity between C4Ad and the corresponding fragment of C3 might be expected to establish a general fold similarity between the two molecules, C4Ad in fact displays a fold that is essentially superimposable on the structure of C3d. By contrast, the electrostatic characteristics of the various faces of the C4Ad molecule show marked differences from the corresponding faces of C3d, likely reflecting the differences in function between C3 and C4. Residues previously predicted to form the major Ch/Rg epitopes were proximately located and accessible on the concave surface of C4Ad. In addition to providing further insights on the current models for the covalent binding reaction, the C4Ad structure allows one to rationalize why C4d is not a ligand for complement receptor 2. Finally the structure allows for the visualization of the face of the molecule containing the binding site for C3b utilized in the assembly of classical pathway C5 convertase.
  Selected figure(s)  
Figure 1.
Figure 1. (a) Top view superposition of the structures of C3d and C4Ad rendered in magenta and gold, respectively, showing the a-a 6 barrel topology of the molecules with 12 helices consecutively alternating from the outside to the inside of the barrel. (b) Side view ribbon representations of the C4Ad structure showing the positions of the thioester-forming residues, Cys991 and Gln994, and the C-terminal isotypic residue Asp1106 (gold ball and stick), all located at the convex face of the molecule. Also shown as ball and stick are the side-chains of the polymorphic amino acid residues Ser1157, Thr1182, Ala1188 and Arg1191. These are proximately located on the concave surface and with the exception of Thr1182 contribute the major Ch/Rg epitopes. Also indicated is a loop in the C4Ad structure (residues 1213-1236) for which no electron density was seen. Residue Ser1217 in this loop is known to be involved in the assembly of the C5 convertase complex (C2a4b3b) by its interaction with C3b. All molecular images in this and subsequent Figures were prepared using MOLSCRIPT[44.] and rendered using POV-RAY(TM).
Figure 5.
Figure 5. Superposition of the backbone representations of C3d (magenta) and C4Ad (gold) in the region corresponding to the putative CR2-binding interface of C3d depicted in the left panel of Figure 4(c). The view is from the perspective of the contacting residues of the CR2 molecule. [33.] The side-chains of C3d N170, which makes the single significant side-chain-side-chain contact with CR2, and the corresponding Q1147 of C4Ad, are also depicted. Asterisked residues P173 and P1144 denote the starting positions of helix 7 in C3d and C4Ad, respectively. The backbone carbonyl oxygen atoms of C3d helix 5 residues I115, L116 and E117, which collectively form the anion hole that interacts with a positively charged arginine side-chain (R84) of CR2, are indicated, as are those of their corresponding C4Ad residues L1089, S1090 and Q1091.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 322, 1103-1115) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21254736 A.Moise, D.Nedelcu, A.Toader, M.Sora, A.Tica, D.E.Ferastraoaru, and I.Constantinescu (2010).
Cytotoxic antibodies--valuable prognostic factor for long term kidney allograft survival.
  J Med Life, 3, 390-395.  
18434316 J.D.Burman, E.Leung, K.L.Atkins, M.N.O'Seaghdha, L.Lango, P.Bernadó, S.Bagby, D.I.Svergun, T.J.Foster, D.E.Isenman, and J.M.van den Elsen (2008).
Interaction of human complement with Sbi, a staphylococcal immunoglobulin-binding protein: indications of a novel mechanism of complement evasion by Staphylococcus aureus.
  J Biol Chem, 283, 17579-17593.  
18697741 N.Doan, and P.G.Gettins (2008).
{alpha}-Macroglobulins Are Present in Some Gram-negative Bacteria: CHARACTERIZATION OF THE {alpha}2-MACROGLOBULIN FROM ESCHERICHIA COLI.
  J Biol Chem, 283, 28747-28756.  
17445829 P.Roversi, O.Lissina, S.Johnson, N.Ahmat, G.C.Paesen, K.Ploss, W.Boland, M.A.Nunn, and S.M.Lea (2007).
The structure of OMCI, a novel lipocalin inhibitor of the complement system.
  J Mol Biol, 369, 784-793.
PDB codes: 2cm4 2cm9
16611328 K.Minami, K.Murata, C.Y.Lee, K.Fox-Talbot, B.A.Wasowska, M.D.Pescovitz, and W.M.Baldwin (2006).
C4d deposition and clearance in cardiac transplants correlates with alloantibody levels and rejection in rats.
  Am J Transplant, 6, 923-932.  
16473914 L.Zhang, and D.Morikis (2006).
Immunophysical properties and prediction of activities for vaccinia virus complement control protein and smallpox inhibitor of complement enzymes using molecular dynamics and electrostatics.
  Biophys J, 90, 3106-3119.  
16524885 Y.Chen, M.Sankala, J.R.Ojala, Y.Sun, A.Tuuttila, D.E.Isenman, K.Tryggvason, and T.Pikkarainen (2006).
A phage display screen and binding studies with acetylated low density lipoprotein provide evidence for the importance of the scavenger receptor cysteine-rich (SRCR) domain in the ligand-binding function of MARCO.
  J Biol Chem, 281, 12767-12775.  
16177781 B.J.Janssen, E.G.Huizinga, H.C.Raaijmakers, A.Roos, M.R.Daha, K.Nilsson-Ekdahl, B.Nilsson, and P.Gros (2005).
Structures of complement component C3 provide insights into the function and evolution of immunity.
  Nature, 437, 505-511.
PDB codes: 2a73 2a74
15598652 J.Bramham, C.T.Thai, D.C.Soares, D.Uhrín, R.T.Ogata, and P.N.Barlow (2005).
Functional insights from the structure of the multifunctional C345C domain of C5 of complement.
  J Biol Chem, 280, 10636-10645.
PDB code: 1xwe
16175181 R.B.Colvin, and R.N.Smith (2005).
Antibody-mediated organ-allograft rejection.
  Nat Rev Immunol, 5, 807-817.  
15342015 G.Hauptmann, and S.Bahram (2004).
Genetics of the central MHC.
  Curr Opin Immunol, 16, 668-672.  
14961982 W.M.Baldwin, E.K.Kasper, A.A.Zachary, B.A.Wasowska, and E.R.Rodriguez (2004).
Beyond C4d: other complement-related diagnostic approaches to antibody-mediated rejection.
  Am J Transplant, 4, 311-318.  
14527961 E.Jelezarova, A.Luginbuehl, and H.U.Lutz (2003).
C3b2-IgG complexes retain dimeric C3 fragments at all levels of inactivation.
  J Biol Chem, 278, 51806-51812.  
12780555 H.E.Feucht (2003).
Complement C4d in graft capillaries -- the missing link in the recognition of humoral alloreactivity.
  Am J Transplant, 3, 646-652.  
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 codes are shown on the right.