Disease-associated N-terminal Complement Factor H Mutations Perturb Cofactor and Decay-accelerating Activities
ABSTRACT Many mutations associated with atypical hemolytic uremic syndrome (aHUS) lie within complement control protein modules 19-20 at the C terminus of the complement regulator factor H (FH). This region mediates preferential action of FH on self, as opposed to foreign, membranes and surfaces. Hence, speculation on disease mechanisms has focused on deficiencies in regulation of complement activation on glomerular capillary beds. Here, we investigate the consequences of aHUS-linked mutations (R53H and R78G) within the FH N-terminal complement control protein module that also carries the I62V variation linked to dense-deposit disease and age-related macular degeneration. This module contributes to a four-module C3b-binding site (FH1-4) needed for complement regulation and sufficient for fluid-phase regulatory activity. Recombinant FH1-4(V62) and FH1-4(I62) bind immobilized C3b with similar affinities (K(D) = 10-14 μM), whereas FH1-4(I62) is slightly more effective than FH1-4(V62) as cofactor for factor I-mediated cleavage of C3b. The mutant (R53H)FH1-4(V62) binds to C3b with comparable affinity (K(D) ∼12 μM) yet has decreased cofactor activities both in fluid phase and on surface-bound C3b, and exhibits only weak decay-accelerating activity for C3 convertase (C3bBb). The other mutant, (R78G)FH1-4(V62), binds poorly to immobilized C3b (K(D) >35 μM) and is severely functionally compromised, having decreased cofactor and decay-accelerating activities. Our data support causal links between these mutations and disease; they demonstrate that mutations affecting the N-terminal activities of FH, not just those in the C terminus, can predispose to aHUS. These observations reinforce the notion that deficiency in any one of several FH functional properties can contribute to the pathogenesis of this disease.
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- "Although clustering in the C-terminal, mutations are reported throughout the molecule. N-terminal mutations in CFH (CCPs 1–4) result in ineffective control of the AP both in the fluid phase and on cell surface (Pechtl et al., 2011). The functional effects of normally secreted genetic variants in other regions of the protein remain to be determined (Kavanagh and Anderson, 2012; Tortajada et al., 2012). "
ABSTRACT: Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace non-functioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the 'gold-standard' for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date.Molecular Immunology 06/2013; 56(3). DOI:10.1016/j.molimm.2013.05.224 · 3.00 Impact Factor
Article: Dense deposit disease[Show abstract] [Hide abstract]
ABSTRACT: Dense deposit disease (DDD) is an orphan disease that primarily affects children and young adults without sexual predilection. Studies of its pathophysiology have shown conclusively that it is caused by fluid-phase dysregulation of the alternative pathway of complement, however the role played by genetics and autoantibodies like C3 nephritic factors must be more thoroughly defined if we are to make an impact in the clinical management of this disease. There are currently no mechanism-directed therapies to offer affected patients, half of whom progress to end stage renal failure disease within 10 years of diagnosis. Transplant recipients face the dim prospect of disease recurrence in their allografts, half of which ultimately fail. More detailed genetic and complement studies of DDD patients may make it possible to identify protective factors prognostic for naïve kidney and transplant survival, or conversely risk factors associated with progression to renal failure and allograft loss. The pathophysiology of DDD suggests that a number of different treatments warrant consideration. As advances are made in these areas, there will be a need to increase healthcare provider awareness of DDD by making resources available to clinicians to optimize care for DDD patients.Molecular Immunology 05/2011; 48(14):1604-10. DOI:10.1016/j.molimm.2011.04.005 · 3.00 Impact Factor
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ABSTRACT: The complement system is a key component of innate and adaptive immune responses. Complement regulation is critical for prevention and control of disease. We have determined the crystal structure of the complement regulatory enzyme human factor I (fI). FI is in a proteolytically inactive form, demonstrating that it circulates in a zymogen-like state despite being fully processed to the mature sequence. Mapping of functional data from mutants of fI onto the structure suggests that this inactive form is maintained by the noncatalytic heavy-chain allosterically modulating activity of the light chain. Once the ternary complex of fI, a cofactor and a substrate is formed, the allosteric inhibition is released, and fI is oriented for cleavage. In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors.Proceedings of the National Academy of Sciences 08/2011; 108(31):12839-44. DOI:10.1073/pnas.1102167108 · 9.81 Impact Factor