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Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
Factor B is a zymogen that carries the catalytic site of the
complement alternative pathway convertases. During C3 convertase
assembly, factor B associates with C3b and is cleaved at a single site
by factor D. The Ba fragment is released, leaving the active complex,
C3bBb. During the course of this process, the protease domain becomes
activated. The type A domain of factor B, also part of Bb, is similar
in structure to the type A domain of the complement receptor and
integrin, CR3. Previously, mutations in the factor B type A domain were
described that impair C3b-binding. This report describes "gain of
function" mutations obtained by substituting factor B type A domain
amino acids with homologous ones derived from the type A domain of CR3.
Replacement of the ßA-
1 Mg2+ binding loop residue D254
with smaller amino acids, especially glycine, increased hemolytic
activity and C3bBb stability. The removal of the oligosaccharide at
position 260, near the Mg2+ binding cleft, when combined
with the D254G substitution, resulted in increased affinity for C3b and
iC3b, a C3b derivative. These findings offer strong evidence for the
direct involvement of the type A domain in C3b binding, and are
suggestive that steric effects of the D254 sidechain and the
N260-linked oligosaccharide may contribute to the regulation of ligand
binding.
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