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Crystal structure of human complement protein C8gamma at 1.2 A resolution reveals a lipocalin fold and a distinct ligand binding site.

Ortlund E, Parker CL, Schreck SF, Ginell S, Minor W, Sodetz JM, Lebioda L
Biochemistry 41 7030-7 (2002)
Cited: 20 times
EuropePMC logo PMID: 12033936

Abstract

C8gamma is a 22-kDa subunit of human C8, which is one of five components of the cytolytic membrane attack complex of complement (MAC). C8gamma is disulfide-linked to a C8alpha subunit that is noncovalently associated with a C8beta chain. In the present study, the three-dimensional structure of recombinant C8gamma was determined by X-ray diffraction to 1.2 A resolution. The structure displays a typical lipocalin fold forming a calyx with a distinct binding pocket that is indicative of a ligand-binding function for C8gamma. When compared to other lipocalins, the overall structure is most similar to neutrophil gelatinase associated lipocalin (NGAL), a protein released from granules of activated neutrophils. Notable differences include a much deeper binding pocket in C8gamma as well as variation in the identity and position of residues lining the pocket. In C8gamma, these residues allow ligand access to a large hydrophobic cavity at the base of the calyx, whereas corresponding residues in NGAL restrict access. This suggests the natural ligands for C8gamma and NGAL are significantly different in size. Cys40 in C8gamma, which forms the disulfide bond to C8alpha, is located in a partially disordered loop (loop 1, residues 38-52) near the opening of the calyx. Access to the calyx may be regulated by movement of this loop in response to conformational changes in C8alpha during MAC formation.

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  1. Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Holmes MA, Paulsene W, Jide X, Ratledge C, Strong RK. Structure 13 29-41 (2005)
  2. Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. Nunn MA, Sharma A, Paesen GC, Adamson S, Lissina O, Willis AC, Nuttall PA. J Immunol 174 2084-2091 (2005)
  3. The 1.8-A crystal structure of alpha1-acid glycoprotein (Orosomucoid) solved by UV RIP reveals the broad drug-binding activity of this human plasma lipocalin. Schönfeld DL, Ravelli RB, Mueller U, Skerra A. J Mol Biol 384 393-405 (2008)
  4. Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit. Slade DJ, Lovelace LL, Chruszcz M, Minor W, Lebioda L, Sodetz JM. J Mol Biol 379 331-342 (2008)
  5. Structure of human C8 protein provides mechanistic insight into membrane pore formation by complement. Lovelace LL, Cooper CL, Sodetz JM, Lebioda L. J Biol Chem 286 17585-17592 (2011)
  6. The structure of OMCI, a novel lipocalin inhibitor of the complement system. Roversi P, Lissina O, Johnson S, Ahmat N, Paesen GC, Ploss K, Boland W, Nunn MA, Lea SM. J Mol Biol 369 784-793 (2007)
  7. Structures of two major allergens, Bla g 4 and Per a 4, from cockroaches and their IgE binding epitopes. Tan YW, Chan SL, Ong TC, Yit LY, Tiong YS, Chew FT, Sivaraman J, Mok YK. J Biol Chem 284 3148-3157 (2009)
  8. Crystal structure of complement protein C8gamma in complex with a peptide containing the C8gamma binding site on C8alpha: implications for C8gamma ligand binding. Lovelace LL, Chiswell B, Slade DJ, Sodetz JM, Lebioda L. Mol Immunol 45 750-756 (2008)
  9. Kinetic proofreading by the cavity system of myoglobin: protection from poisoning. Radding W, Phillips GN. Bioessays 26 422-433 (2004)
  10. The gamma subunit of the eighth complement component (C8) in rainbow trout. Papanastasiou AD, Zarkadis IK. Dev Comp Immunol 30 485-491 (2006)
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