Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation.
Vaccinia virus complement control protein (VCP), a homolog of the regulators of the complement activation family of proteins, inhibits complement activation through mechanisms similar to human fluid-phase complement regulators factor H and C4b-binding protein. VCP has a heparin-binding activity that assists vaccinia in host interactions. Interaction with cell-surface polyanions like heparin is centrally important in the functioning of fluid-phase complement regulators and is the basis of host-target discrimination by the alternative pathway. We report the structure of VCP in complex with a heparin decasaccharide, which reveals changes in VCP that might be pertinent to complement regulation. Properties that VCP shares with fluid-phase complement regulators suggest that such conformational changes may be of relevance in the functioning of other complement regulators. Additionally, comparison of VCP-heparin interactions with potentially similar interactions in factor H might enable understanding of the structural basis of familial hemolytic uremic syndrome, attributed to mutational disruption of heparin and C3b binding by factor H.
Ganesh
Vannakambadi K
VK
Center for Biophysical Science and Engineering, University of Alabama at Birmingham, Birmingham, AL 35294-4400, USA.
Smith
Scott A
SA
Kotwal
Girish J
GJ
Murthy
Krishna H M
KH
D000595:Amino Acid Sequence; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
C493495:CFH protein, human; D010446:Peptide Fragments; D014764:Viral Proteins; C066459:complement-control protein, Vaccinia virus; D003179:Complement C3b; D017242:Complement Factor H; D006493:Heparin