Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 7, Pages 4295-4306Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.527416
Keywords
Complement System; Innate Immunity; Oxidative Stress; Pathogenesis; Protein Chemical Modification; CFH; aHUS; Malondialdehyde; Surface Recognition; Thrombotic Microangiopathy
Categories
Funding
- Sigrid Juselius Foundation
- Academy of Finland [128646, 255922, 259793]
- Academy of Finland (AKA) [255922, 259793, 128646, 259793, 255922, 128646] Funding Source: Academy of Finland (AKA)
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Background: Malondialdehyde (MDA) released during oxidative stress modifies proteins covalently. Results: The C terminus of complement regulator factor H binds negative patches on MDA-modified proteins, and aHUS-related mutations affect the interaction. Conclusion: Defects in factor H binding to MDA-modified surfaces might allow deleterious complement activation on them. Significance: MDA-modifications are potentially a new factor in aHUS pathogenesis. Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characterized by uncontrolled complement activation against endothelial and blood cells. Mutations in the C-terminal target recognition domains 19-20 of complement regulator factor H (FH) are strongly associated with aHUS, but the mechanisms triggering disease onset have remained unresolved. Here we report that several aHUS-related mutations alter the binding of FH19-20 to proteins where lysines have reacted with malondialdehyde (MDA). Although FH19-20 did not interact with MDA-modified hexylamine, lysine-containing peptides, or a proteolytically degraded protein, it bound to MDA-modified polylysine. This suggests that FH19-20 recognizes only clustered MDA adducts. Binding of MDA-modified BSA to FH19-20 was ionic by nature, depended on positive residues of FH19-20, and competed with the polyanions heparin and DNA. This could not be explained with the mainly neutral adducts known to form in MDA modification. When positive charges of lysines were eliminated by acetic anhydride instead of MDA, the acetylated BSA started to bind FH19-20. Together, these results indicate that negative charges on the modified proteins dominate the interaction with FH19-20. This is beneficial for the physiological function of FH because by binding to the negative charges of the modified target, FH could prevent excess complement activation initiated by naturally occurring antibodies recognizing MDA epitopes with multiple different structures. We propose that oxidative stress leading to formation of MDA adducts is a common feature for triggers of aHUS and that failure of FH in protecting MDA-modified surfaces from complement activation is involved in the pathogenesis of the disease.
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