PDBsum entry 2qqh

Go to PDB code: 
protein ligands metals links
Immune system, membrane protein PDB id
Protein chain
304 a.a. *
SO4 ×3
Waters ×44
* Residue conservation analysis
PDB id:
Name: Immune system, membrane protein
Title: Structure of c8a-macpf reveals mechanism of membrane attack in complement immune defense
Structure: Complement component c8 alpha chain. Chain: a. Synonym: complement component 8 subunit alpha. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: c8a. Expressed in: escherichia coli. Expression_system_taxid: 562.
2.50Å     R-factor:   0.256     R-free:   0.287
Authors: M.A.Hadders,P.Gros
Key ref:
M.A.Hadders et al. (2007). Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science, 317, 1552-1554. PubMed id: 17872444 DOI: 10.1126/science.1147103
26-Jul-07     Release date:   25-Sep-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P07357  (CO8A_HUMAN) -  Complement component C8 alpha chain
584 a.a.
304 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 14 residue positions (black crosses)


DOI no: 10.1126/science.1147103 Science 317:1552-1554 (2007)
PubMed id: 17872444  
Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense.
M.A.Hadders, D.X.Beringer, P.Gros.
Membrane attack is important for mammalian immune defense against invading microorganisms and infected host cells. Proteins of the complement membrane attack complex (MAC) and the protein perforin share a common MACPF domain that is responsible for membrane insertion and pore formation. We determined the crystal structure of the MACPF domain of complement component C8alpha at 2.5 angstrom resolution and show that it is structurally homologous to the bacterial, pore-forming, cholesterol-dependent cytolysins. The structure displays two regions that (in the bacterial cytolysins) refold into transmembrane beta hairpins, forming the lining of a barrel pore. Local hydrophobicity explains why C8alpha is the first complement protein to insert into the membrane. The size of the MACPF domain is consistent with known C9 pore sizes. These data imply that these mammalian and bacterial cytolytic proteins share a common mechanism of membrane insertion.
  Selected figure(s)  
Figure 1.
Fig. 1. Structure of human C8 -MACPF. C representation of C8 -MACPF (A) and intermedilysin (PDB accession code 1s3r) (B) in two views. The top and bottom halves of the molecule are denoted d1 (blue) and d3 (brown), respectively. The central kinked ß sheet (part of both d1 and d3) is shown in green. The additional domains d2 and d4 in intermedilysin are shown in gray. Figures are produced with PyMOL (30).
Figure 2.
Fig. 2. Comparison of putative transmembrane regions. (A) Cartoon diagrams of domains d3 of C8 -MACPF (left) and intermedilysin (right). The putative ß hairpin regions ß1-ß2 and TMH1 are colored in dark brown, and ß3-ß4 and TMH2 are colored in light brown. (B) Sequence alignment of (i) the ß1-ß2 and ß3-ß4 regions of C8 , C9, and perforin (Perf) and (ii) TMH1 and TMH2 of perfringolysin (PFO) and intermedilysin (ILY). Residues (31) are colored according to character: hydrophobic (green), positively charged (blue), negatively charged (red), and hydrophilic (white). Yellow indicates cysteine residues. Secondary structure elements, as observed for C8 -MACPF and intermedilysin, are indicated. Putative transmembrane regions are indicated by gray boxes.
  The above figures are reprinted by permission from the AAAs: Science (2007, 317, 1552-1554) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20889983 T.Praper, A.Sonnen, G.Viero, A.Kladnik, C.J.Froelich, G.Anderluh, M.Dalla Serra, and R.J.Gilbert (2011).
Human perforin employs different avenues to damage membranes.
  J Biol Chem, 286, 2946-2955.  
21352921 Y.H.Shi, J.Chen, C.H.Li, H.Y.Yang, and X.J.Lu (2011).
The establishment of a library screening method based on yeast two-hybrid system and its use to determine the potential interactions of liver proteins in ayu, Plecoglossus altivelis.
  Fish Shellfish Immunol, 30, 1184-1187.  
20075937 A.J.Brennan, J.Chia, J.A.Trapani, and I.Voskoboinik (2010).
Perforin deficiency and susceptibility to cancer.
  Cell Death Differ, 17, 607-615.  
  20539776 B.F.Kafsack, and V.B.Carruthers (2010).
Apicomplexan perforin-like proteins.
  Commun Integr Biol, 3, 18-23.  
  20100082 F.Zhou (2010).
Perforin: more than just a pore-forming protein.
  Int Rev Immunol, 29, 56-76.  
  20536557 J.Lieberman (2010).
Granzyme A activates another way to die.
  Immunol Rev, 235, 93.  
20351143 L.D.Taylor, D.E.Nelson, D.W.Dorward, W.M.Whitmire, and H.D.Caldwell (2010).
Biological characterization of Chlamydia trachomatis plasticity zone MACPF domain family protein CT153.
  Infect Immun, 78, 2691-2699.  
20457744 L.Holm, and P.Rosenström (2010).
Dali server: conservation mapping in 3D.
  Nucleic Acids Res, 38, W545-W549.  
  20944225 Q.Xu, P.Abdubek, T.Astakhova, H.L.Axelrod, C.Bakolitsa, X.Cai, D.Carlton, C.Chen, H.J.Chiu, T.Clayton, D.Das, M.C.Deller, L.Duan, K.Ellrott, C.L.Farr, J.Feuerhelm, J.C.Grant, A.Grzechnik, G.W.Han, L.Jaroszewski, K.K.Jin, H.E.Klock, M.W.Knuth, P.Kozbial, S.S.Krishna, A.Kumar, W.W.Lam, D.Marciano, M.D.Miller, A.T.Morse, E.Nigoghossian, A.Nopakun, L.Okach, C.Puckett, R.Reyes, H.J.Tien, C.B.Trame, H.van den Bedem, D.Weekes, T.Wooten, A.Yeh, J.Zhou, K.O.Hodgson, J.Wooley, M.A.Elsliger, A.M.Deacon, A.Godzik, S.A.Lesley, and I.A.Wilson (2010).
Structure of a membrane-attack complex/perforin (MACPF) family protein from the human gut symbiont Bacteroides thetaiotaomicron.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 66, 1297-1305.
PDB code: 3kk7
21037563 R.H.Law, N.Lukoyanova, I.Voskoboinik, T.T.Caradoc-Davies, K.Baran, M.A.Dunstone, M.E.D'Angelo, E.V.Orlova, F.Coulibaly, S.Verschoor, K.A.Browne, A.Ciccone, M.J.Kuiper, P.I.Bird, J.A.Trapani, H.R.Saibil, and J.C.Whisstock (2010).
The structural basis for membrane binding and pore formation by lymphocyte perforin.
  Nature, 468, 447-451.
PDB code: 3nsj
20860583 S.C.Kondos, T.Hatfaludi, I.Voskoboinik, J.A.Trapani, R.H.Law, J.C.Whisstock, and M.A.Dunstone (2010).
The structure and function of mammalian membrane-attack complex/perforin-like proteins.
  Tissue Antigens, 76, 341-351.  
20017192 S.M.Black, M.E.Schott, B.H.Batdorf, B.A.Benson, M.S.Rutherford, B.K.Levay-Young, and A.P.Dalmasso (2010).
IL-4 induces protection of vascular endothelial cells against killing by complement and melittin through lipid biosynthesis.
  Eur J Immunol, 40, 803-812.  
20043185 U.Hinz, R.Apweiler, M.J.Martin, C.O'Donovan, M.Magrane, Y.Alam-Faruque, R.Antunes, D.Barrell, B.Bely, M.Bingley, D.Binns, L.Bower, P.Browne, W.M.Chan, E.Dimmer, R.Eberhardt, A.Fedotov, R.Foulger, J.Garavelli, R.Huntley, J.Jacobsen, M.Kleen, K.Laiho, R.Leinonen, D.Legge, Q.Lin, W.Liu, J.Luo, S.Orchard, S.Patient, D.Poggioli, M.Pruess, M.Corbett, G.di Martino, M.Donnelly, P.van Rensburg, A.Bairoch, L.Bougueleret, I.Xenarios, S.Altairac, A.Auchincloss, G.Argoud-Puy, K.Axelsen, D.Baratin, M.C.Blatter, B.Boeckmann, J.Bolleman, L.Bollondi, E.Boutet, S.B.Quintaje, L.Breuza, A.Bridge, Castro, L.Ciapina, D.Coral, E.Coudert, I.Cusin, F.David, G.Delbard, M.Doche, D.Dornevil, P.D.Roggli, S.Duvaud, A.Estreicher, L.Famiglietti, M.Feuermann, S.Gehant, N.Farriol-Mathis, S.Ferro, E.Gasteiger, A.Gateau, V.Gerritsen, A.Gos, N.Gruaz-Gumowski, U.Hinz, C.Hulo, N.Hulo, J.James, S.Jimenez, F.Jungo, T.Kappler, G.Keller, C.Lachaize, L.Lane-Guermonprez, P.Langendijk-Genevaux, V.Lara, P.Lemercier, D.Lieberherr, T.d.e. .O.Lima, V.Mangold, X.Martin, P.Masson, M.Moinat, A.Morgat, A.Mottaz, S.Paesano, I.Pedruzzi, S.Pilbout, V.Pillet, and S.Poux (2010).
From protein sequences to 3D-structures and beyond: the example of the UniProt knowledgebase.
  Cell Mol Life Sci, 67, 1049-1064.  
20153530 V.Rossi, Y.Wang, and A.F.Esser (2010).
Topology of the membrane-bound form of complement protein C9 probed by glycosylation mapping, anti-peptide antibody binding, and disulfide modification.
  Mol Immunol, 47, 1553-1560.  
19048311 A.Stavrakoudis (2009).
A disulfide linked model of the complement protein C8gamma complexed with C8alpha indel peptide.
  J Mol Model, 15, 165-171.  
19095897 B.F.Kafsack, J.D.Pena, I.Coppens, S.Ravindran, J.C.Boothroyd, and V.B.Carruthers (2009).
Rapid membrane disruption by a perforin-like protein facilitates parasite exit from host cells.
  Science, 323, 530-533.  
19487666 J.Chia, K.P.Yeo, J.C.Whisstock, M.A.Dunstone, J.A.Trapani, and I.Voskoboinik (2009).
Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer.
  Proc Natl Acad Sci U S A, 106, 9809-9814.  
19292457 J.J.Flanagan, R.K.Tweten, A.E.Johnson, and A.P.Heuck (2009).
Cholesterol exposure at the membrane surface is necessary and sufficient to trigger perfringolysin O binding.
  Biochemistry, 48, 3977-3987.  
19442503 M.Bischofberger, M.R.Gonzalez, and F.G.van der Goot (2009).
Membrane injury by pore-forming proteins.
  Curr Opin Cell Biol, 21, 589-595.  
19614666 M.S.Roiko, and V.B.Carruthers (2009).
New roles for perforins and proteases in apicomplexan egress.
  Cell Microbiol, 11, 1444-1452.  
19098006 R.Kayed, A.Pensalfini, L.Margol, Y.Sokolov, F.Sarsoza, E.Head, J.Hall, and C.Glabe (2009).
Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer.
  J Biol Chem, 284, 4230-4237.  
19095652 S.Mukherjee, C.L.Partch, R.E.Lehotzky, C.V.Whitham, H.Chu, C.L.Bevins, K.H.Gardner, and L.V.Hooper (2009).
Regulation of C-type Lectin Antimicrobial Activity by a Flexible N-terminal Prosegment.
  J Biol Chem, 284, 4881-4888.  
18564372 C.J.Rosado, S.Kondos, T.E.Bull, M.J.Kuiper, R.H.Law, A.M.Buckle, I.Voskoboinik, P.I.Bird, J.A.Trapani, J.C.Whisstock, and M.A.Dunstone (2008).
The MACPF/CDC family of pore-forming toxins.
  Cell Microbiol, 10, 1765-1774.  
18440555 D.J.Slade, L.L.Lovelace, M.Chruszcz, W.Minor, L.Lebioda, and J.M.Sodetz (2008).
Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit.
  J Mol Biol, 379, 331-342.
PDB code: 2rd7
18502634 E.Ikonen, and M.Jansen (2008).
Cellular sterol trafficking and metabolism: spotlight on structure.
  Curr Opin Cell Biol, 20, 371-377.  
18772390 F.C.Kurschus, E.Fellows, E.Stegmann, and D.E.Jenne (2008).
Granzyme B delivery via perforin is restricted by size, but not by heparan sulfate-dependent endocytosis.
  Proc Natl Acad Sci U S A, 105, 13799-13804.  
18778941 G.Anderluh, and J.H.Lakey (2008).
Disparate proteins use similar architectures to damage membranes.
  Trends Biochem Sci, 33, 482-490.  
18390664 S.E.Gelber, J.L.Aguilar, K.L.Lewis, and A.J.Ratner (2008).
Functional and phylogenetic characterization of Vaginolysin, the human-specific cytolysin from Gardnerella vaginalis.
  J Bacteriol, 190, 3896-3903.  
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.