Crystal Structure of Human Complement Protein C8 at 1.2 Å Resolution Reveals a Lipocalin Fold and a Distinct Ligand Binding Si
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- 作者：Eric Ortlund ; Chasta L. Parker ; Steven F. Schreck ; Steve Ginell ; Wladek Minor ; James M. Sodetz ; and Lukasz Lebioda
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：June 4, 2002
- 年：2002
- 卷：41
- 期：22
- 页码：7030 - 7037
- 全文大小：640K
- 年卷期：v.41,no.22(June 4, 2002)
- ISSN：1520-4995
文摘
C8
is a 22-kDa subunit of human C8, which is one of five components of the cytolyticmembrane attack complex of complement (MAC). C8 is disulfide-linked to a C8
subunit that isnoncovalently associated with a C8
chain. In the present study, the three-dimensional structure ofrecombinant C8 was determined by X-ray diffraction to 1.2 Å resolution. The structure displays a typicallipocalin fold forming a calyx with a distinct binding pocket that is indicative of a ligand-binding functionfor C8. When compared to other lipocalins, the overall structure is most similar to neutrophil gelatinaseassociated lipocalin (NGAL), a protein released from granules of activated neutrophils. Notable differencesinclude a much deeper binding pocket in C8 as well as variation in the identity and position of residueslining the pocket. In C8, these residues allow ligand access to a large hydrophobic cavity at the base ofthe calyx, whereas corresponding residues in NGAL restrict access. This suggests the natural ligands forC8 and NGAL are significantly different in size. Cys40 in C8, which forms the disulfide bond to C8,is located in a partially disordered loop (loop 1, residues 38-52) near the opening of the calyx. Accessto the calyx may be regulated by movement of this loop in response to conformational changes in C8during MAC formation.
is a 22-kDa subunit of human C8, which is one of five components of the cytolyticmembrane attack complex of complement (MAC). C8 is disulfide-linked to a C8 subunit that isnoncovalently associated with a C8 chain. In the present study, the three-dimensional structure ofrecombinant C8 was determined by X-ray diffraction to 1.2 Å resolution. The structure displays a typicallipocalin fold forming a calyx with a distinct binding pocket that is indicative of a ligand-binding functionfor C8. When compared to other lipocalins, the overall structure is most similar to neutrophil gelatinaseassociated lipocalin (NGAL), a protein released from granules of activated neutrophils. Notable differencesinclude a much deeper binding pocket in C8 as well as variation in the identity and position of residueslining the pocket. In C8, these residues allow ligand access to a large hydrophobic cavity at the base ofthe calyx, whereas corresponding residues in NGAL restrict access. This suggests the natural ligands forC8 and NGAL are significantly different in size. Cys40 in C8, which forms the disulfide bond to C8,is located in a partially disordered loop (loop 1, residues 38-52) near the opening of the calyx. Accessto the calyx may be regulated by movement of this loop in response to conformational changes in C8during MAC formation.