Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation.
The outbreak of monkeypox in the Unites States in the summer of 2003 was the first occurrence of this smallpox-like disease outside of Africa. This limited human epidemic resulted from cross-infection of prairie dogs by imported African rodents. Although there were no human fatalities, this outbreak illustrates that monkeypox is an emerging natural infection and a potential biological weapon. We characterized a virulence factor expressed by monkeypox (monkeypox inhibitor of complement enzymes or MOPICE). We also compared its structure and regulatory function to homologous complement regulatory proteins of variola (SPICE) and vaccinia (VCP). In multiple expression systems, 5-30% of MOPICE, SPICE, and VCP consisted of function-enhancing disulfide-linked homodimers. Mammalian cells infected with vaccinia virus also expressed VCP dimers. MOPICE bound human C3b/C4b intermediate to that of SPICE and VCP. Cofactor activity of MOPICE was similar to VCP, but both were approximately 100-fold less efficient than SPICE. SPICE and VCP, but not MOPICE, possessed decay-accelerating activity for the C3 and C5 convertases of the classical pathway. Additionally, all three regulators possessed heparin-binding capability. These studies demonstrate that MOPICE regulates human complement and suggest that dimerization is a prominent feature of these virulence factors. Thus, our data add novel information relative to the functional repertoire of these poxviral virulence factors. Furthermore, targeting and neutralizing these complement regulatory active sites via mAbs is a therapeutic approach that may enhance protection against smallpox.
Liszewski
M Kathryn
MK
Department of Medicine/Division of Rheumatology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Leung
Marilyn K
MK
Hauhart
Richard
R
Buller
R Mark L
RM
Bertram
Paula
P
Wang
Xuefeng
X
Rosengard
Ariella M
AM
Kotwal
Girish J
GJ
Atkinson
John P
JP
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003166:Complement Activating Enzymes / Q000378:metabolism; D003179:Complement C3b / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015935:Complement C4b / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006224:Cricetinae; D019281:Dimerization; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D008993:Monkeypox virus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D014616:Vaccinia virus / Q000737:chemistry* / Q000276:immunology; D012901:Variola virus / Q000737:chemistry* / Q000276:immunology
D003179:Complement C3b; D015935:Complement C4b; D006493:Heparin; D003166:Complement Activating Enzymes