Crystal structure of human complement protein C8γ at 1.2 Å resolution reveals a lipocalin fold and a distinct ligand binding site

C8γ is a 22-kDa subunit of human C8, which is one of five components of the cytolytic membrane attack complex of complement (MAC). C8γ is disulfide-linked to a C8α subunit that is noncovalently associated with a C8β chain. In the present study, the three-dimensional structure of recombinant C8γ was determined by X-ray diffraction to 1.2 Å 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 C8γ. 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 C8γ as well as variation in the identity and position of residues lining the pocket. In C8γ, 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 C8γ and NGAL are significantly different in size. Cys⁴⁰ in C8γ, which forms the disulfide bond to C8α, 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 C8α during MAC formation.