3kxv
From Proteopedia
Structure of complement Factor H variant Q1139A
Structural highlights
Disease[CFAH_HUMAN] Genetic variations in CFH are associated with basal laminar drusen (BLD) [MIM:126700]; also known as drusen of Bruch membrane or cuticular drusen or grouped early adult-onset drusen. Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch membrane. Basal laminar drusen refers to an early adult-onset drusen phenotype that shows a pattern of uniform small, slightly raised yellow subretinal nodules randomly scattered in the macula. In later stages, these drusen often become more numerous, with clustered groups of drusen scattered throughout the retina. In time these small basal laminar drusen may expand and ultimately lead to a serous pigment epithelial detachment of the macula that may result in vision loss. Defects in CFH are the cause of complement factor H deficiency (CFHD) [MIM:609814]. A disorder that can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3, and a decrease in other terminal complement components, indicating activation of the alternative complement pathway. It is associated with a number of renal diseases with variable clinical presentation and progression, including membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome.[1] [2] [3] [4] [5] [6] [7] [8] Defects in CFH are a cause of susceptibility to hemolytic uremic syndrome atypical type 1 (AHUS1) [MIM:235400]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.[9] [10] [11] [12] [13] [14] [15] [16] Genetic variation in CFH is associated with age-related macular degeneration type 4 (ARMD4) [MIM:610698]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid (known as drusen) that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.[17] Function[CFAH_HUMAN] Factor H functions as a cofactor in the inactivation of C3b by factor I and also increases the rate of dissociation of the C3bBb complex (C3 convertase) and the (C3b)NBB complex (C5 convertase) in the alternative complement pathway. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFactor H (FH) regulates the alternative pathway of complement in plasma and mediates discrimination of cellular surfaces to alternative pathway activators and non-activators. The carboxyl-terminal domains 19 and 20 of FH are essential in target discrimination and are known to contain binding sites for the C3d part of C3b, heparin, and endothelial cells. Mutations in FH19-20 are frequently found in patients with atypical haemolytic uremic syndrome (aHUS). Most aHUS-associated and some other mutations have been shown to lead to impaired binding to C3d and C3b by the recombinant FH19-20 fragment. Most of these mutated residues, such as R1203, are located close to each other in domain 20 but some, such as Q1139, are located in domain 19. We generated mutant proteins Q1139A and R1203A of FH19-20 and showed that their binding to C3d and C3b was clearly impaired. To show that the effects on C3d/C3b binding are due to direct interactions rather than structural changes, we solved the X-ray crystal structures of the R1203A and Q1139A mutant proteins at 1.65 and 2.0A, respectively. Neither of the mutations caused any overall structural changes in FH19-20. It is thus evident that Q1139 in domain 19 and R1203 in domain 20 are directly involved in binding to the C3d part of C3b and therefore both the domains are involved in the interaction with C3d and C3b. This explains why several aHUS-associated FH mutations are found within domain 19 in addition to domain 20. Both domain 19 and domain 20 of factor H are involved in binding to complement C3b and C3d.,Bhattacharjee A, Lehtinen MJ, Kajander T, Goldman A, Jokiranta TS Mol Immunol. 2010 May;47(9):1686-91. Epub 2010 Apr 7. PMID:20378178[18] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Bhattacharjee, A | Goldman, A | Jokiranta, T S | Kajander, T | Lehtinen, M J | Atypical hemolytic uremic syndrome | Cfh | Complement alternative pathway | Complement control protein module | Complement regulator | Disease mutation | Glycoprotein | Immune response | Immune system | Innate immunity | Renal disease | Scr domain | Short consensus repeat domain | Sushi domain
