Abstract
Factor H (FH) is the major regulator of C3b in the alternative pathway of the complement system in immunity. FH comprises 20 short complement regulator (SCR) domains, including eight glycans, and its Y402H polymorphism predisposes those who carry it to age-related macular degeneration. To better understand FH complement binding and self-association, we have studied the solution structures of both the His-402 and Tyr-402 FH allotypes. Analytical ultracentrifugation revealed that up to 12% of both FH allotypes self-associate, and this was confirmed by small-angle X-ray scattering (SAXS), MS, and surface plasmon resonance analyses. SAXS showed that monomeric FH has a radius of gyration (Rg) of 7.2–7.8 nm and a length of 25 nm. Starting from known structures for the SCR domains and glycans, the SAXS data were fitted using Monte Carlo methods to determine atomistic structures of monomeric FH. The analysis of 29,715 physically realistic but randomized FH conformations resulted in 100 similar best-fit FH structures for each allotype. Two distinct molecular structures resulted that showed either an extended N-terminal domain arrangement with a folded-back C terminus or an extended C terminus and a folded-back N terminus. These two structures are the most accurate to date for glycosylated full-length FH. To clarify FH functional roles in host protection, crystal structures for the FH complexes with C3b and C3dg revealed that the extended N-terminal conformation accounted for C3b fluid-phase regulation, the extended C-terminal conformation accounted for C3d binding, and both conformations accounted for bivalent FH binding to glycosaminoglycans on the target cell surface.
Highlights
Factor H (FH) is the major regulator of C3b in the alternative pathway of the complement system in immunity
To clarify FH functional roles in host protection, crystal structures for the FH complexes with C3b and C3dg revealed that the extended N-terminal conformation accounted for C3b fluid-phase regulation, the extended C-terminal conformation accounted for C3d binding, and both conformations accounted for bivalent FH binding to glycosaminoglycans on the target cell surface
FH was genotyped for both Y402H and I62V polymorphisms, with our focus on the former, whereas the presence of Val-62 or Ile-62 in the FH samples was noted for completion but was not investigated further [56]
Summary
Factor H (FH) is the major regulator of C3b in the alternative pathway of the complement system in immunity. Tel.: 020-7679-7048; Fax: To prevent unwanted C3b-mediated host cell damage, complement factor H (FH) regulates complement by acting as a cofactor for factor I (FI) to cleave C3b [1,2,3], competing with factor B (FB) to interfere with the formation of the C3 convertase C3bBb [4], and accelerating the decay of the C3bBb complex [2, 5]. These activities occur in the fluid phase and less effectively at the host cell surface [6]. Carbohydrates, cellular materials, and over 200 proteins, including FH and other complement components [10, 15, 16]
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