Factor h family proteins and human diseases book pdf

Review rnabinding proteins in human genetic disease. Neisseria meningitidis recruits factor h using protein. Neisseria meningitidis is a human adapted pathogen of global importance as a leading cause of bacterial meningitis and septic shock5. The plasmodium falciparum blood stages acquire factor h.

Frontiers factor h family proteins in complement evasion. Complement factor h related proteins cfhrs sciencedirect. Disease linked mutations in factor h reveal pivotal role of cofactor. One of the central complement regulators is factor h, which belongs to a protein family that includes cfhl1 and five factor h related cfhr proteins. Surfaceassociated m protein is a major virulence factor in streptococcus pyogenes which confers bacterial resistance to phagocytosis. Factor h related proteins cfhrs are plasma glycoproteins related in structure and antigenicity to each other and to the complement inhibitory protein factor h. Recent evidence shows that factor h family proteins factor h and cfhrs are associated with diverse and severe human diseases and are also used by human pathogenic microbes for complement evasion. Each single gene of the family members cfhr1, cfhr2, cfhr3, cfhr4, cfhr5 and factor h is located on a distinct segment on human chromosome 1q32 within the rca.

All factor h family proteins share common features. The complement regulator factor h is the best characterized molecule of this gene family. Recent evidence shows that 29 factor h family proteins factor h and cfhrs are associated with diverse and severe human 30 diseases, and are also utilized by human pathogenic microbes for complement evasion. Proteinprotein interactions in human disease, volume 111, part b, promotes further research and development in the protein interaction network in order to identify critical proteins involved in the etiology of human diseases and locate new protein targets for drug development. Factor h family proteins in complement evasion of microorganisms. Its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed. Proteinprotein interactions in human disease, part b. We recently showed that the gametes of the human malaria parasite plasmodium falciparum bind factor h fh from the blood meal of the mosquito vector to assure successful sexual reproduction, which takes places in the mosquito midgut. Factor h family proteins and human diseases sciencedirect. Human factor h related protein 2 cfhr2 regulates complement activation. First, the gene for cfh is located on chromosome 1q31, a region that had been implicated in amd by six independent linkage scans 48, 20.

Surface proteins of streptococcus agalactiae and related. Since many complementmediated diseases have an onset during childhood, it is. Ris of factor h fh, the crucial fluidphase regulator, and the fhrelated. Complement and kidney disease peter f zipfel springer. Pathogenbound fh family proteins can also mediate adhesion and facilitate the invasion of host cells. Association of genetic variants in complement factor h and.

Thus, this volume is of considerable interest to protein chemists, pharmacologists, cell biologists, immunologists. Reference intervals of factor h and factor hrelated proteins in. The major autoantibody epitope on factor h in atypical hemolytic. Although the nglycans linked to factor h have been studied ritchie et al. Journals az books and reference advertising media kit. Jci human c3 glomerulopathy provides unique insights. Similarly, the factor h binding site was localized to the crepeat region of the m6 protein fischetti et al. The human pathogen neisseria meningitidis, a leading cause of bacterial meningitis and septic shock, possesses a surface protein, factor h binding protein or.

According to them, mutations in enzymes are predominantly recessive, while mutations in receptors, transcription factors and structural proteins are often dominant. The journal of infectious diseases, volume 205, issue 6, 15 march 2012, pages 9951004. Factor h is a complement regulatory protein that controls activation of the alternative pathway in the fluid phase and on cell surfaces. Familial hus or ttp was diagnosed in patients for whom at least two members of the family were affected by the disease at least 6. Such proteins are found in most mammals but their number and domain composition vary. It is a large 155 kilodaltons, soluble glycoprotein that circulates in human plasma at typical concentrations of 200300 micrograms per milliliter. Intriguingly, distinct genetic changes in factor h fh, a key regulator of the alternative pathway, are associated with hemolytic uremic syndrome hus, membranoproliferative glomerulonephritis dense deposit disease, or agerelated macular degeneration amd. Factor h belongs to a family of proteins built from ccps. 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. Elegant in vitro studies of the mutant and normal variants demonstrate an unexpected mechanism of action of fhr1, wherein homodimeration and heterooligomerization. Pdf factor h family proteins in complement evasion of.

The molecule is made up of 20 complement control protein ccp modules also. It is a single chain, 155 kda glycoprotein that is present in human plasma in a concentration of about 500. Molecules acting as complement inhibitors are shown in red. Factor h and factor h related protein 1 bind to human. Leptospiral immunoglobulinlike proteins interact with. The ris of these fh family proteins now serve to support the. Complement factor h family proteins in their noncanonical role as modulators of cellular functions. Deficiency of complement factor hrelated proteins and.

Complement control protein are proteins that interact with components of the complement system the complement system is tightly regulated by a network of proteins known as regulators of complement activation rca that help distinguish target cells as self or nonself. Factor h is a member of the regulators of complement activation family and is a complement. Factor h family proteins include factor h, cfhl1, and five factor h related proteins1,10. Zipfel2,3 1junior research group cellular immunobiology, leibniz institute for natural product research and infection biologyhans kno. This chapter summarizes our current knowledge on the human factor h related proteins.

Diseaselinked mutations in factor h reveal pivotal role of cofactor. Factor h related proteins comprise a group of five plasma proteins. Recruitment of human c1 esterase inhibitor controls complement. Complement factor h polymorphism in agerelated macular. A large panel of distinct human kidney diseases is caused by defective. Complement pathways and the human factor h fh protein family. Agerelated macular degeneration amd is a leading cause of blindness in older people.

The ones marked may be different from the article in the profile. We report an extensive survey and phylogenetic analysis of the diversity of fhbp genes and predicted protein sequences in invasive clinical isolates obtained. Recent human linkage data implicate a role for a group of genes, encoding a family designated factor h related fhr proteins, in the pathogenesis of sle. Due to neisserial strain variation, the vaccines currently available for meningococcal disease are only effective against subsets of strains and do not provide universal protection6, 7. Factor h binds to c3b by displacing bb from c3 convertases and acts as a cofactor for factor i, which cleaves c3b to its inactive form, ic3b. The book adopts a unique approach to the topic compared with other biochemistry textbooks currently available, in that each biochemical subject is introduced by a human disease relating the biochemical principles to be developed in that chapter. Recombinant forms of neisseria meningitidis human factor h binding protein fhbp are undergoing clinical trials in candidate vaccines against invasive meningococcal serogroup b disease. Systemic lupus erythematosus sle, a complex polygenic autoimmune disease, is associated with increased complement activation. Genetic analyses have identified mutations in complement regulators that are associated with these diseases. Complement factor h binds malondialdehyde epitopes and. Sequence diversity of the factor h binding protein vaccine. Deficiency of complement factor h related proteins and autoantibodypositive hemolytic uremic syndrome in an infant with combined partial deficiencies and autoantibodies to complement factor h and adamts. For example, the genes encoding these proteins are all located in chromosome 1q32 at the regulators of complement activation locus.

Factor h related protein 5 fhr5 is a newly identified member of the human factor h family of proteins and a component of normal human plasma. Haemolytic uraemic syndrome hus is a disease associated with. Functional anatomy of complement factor h biochemistry acs. Cfhr1, cfhr2, cfhr3, cfhr4 and cfhr5, and each member of this group binds to the central complement component c3b. Factor h is a 155kda glycoprotein containing nine potential nglycosylation sites. Factor h is a member of the regulators of complement activation family and is a complement control protein. Functional anatomy of complement factor h biochemistry. It is evident that a defective or deregulated complement system results in kidney diseases. Pdf human factor hrelated protein 2 cfhr2 regulates. Disease description a disorder that can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure.

Variants of genes encoding complement regulator factor h cfh and five cfhrelated proteins cfhr1cfhr5 within the chromosome 1q32 locus linked to sle, have been associated with multiple human diseases and may contribute to dysregulated complement activation. An important role of complement effector and regulatory proteins in pathological settings of the kidney has been demonstrated. One goal of the hapmap project is to help reserachers find snps associated with human disease. Lfha, a novel factor hbinding protein of leptospira. Large quantities of biologically active human factor h, potentially suitable for. Several lines of evidence support the hypothesis that sequence polymorphisms in cfh can lead to amd. However, promising novel antigens have been identified8, including factor h. A subset of this family of proteins, complement control proteins ccp, are characterized by domains of conserved. B the five human fhrelated fhr proteins retained domains homologous to complement control protein domains 69 and 1820 of fh showed by vertical alignment.

A schematic overview of the major complement activation and regulation pathways. A large panel of distinct human kidney diseases is caused by defective complement control. Investigating the roles of factor hrelated proteins in. Cfh complement factor h precursor homo sapiens human. Protein interactions in human genetic diseases genome. The study in this issue of the jci by tortajada et al. One of the central complement regulators is factor h, which belongs to a protein family that includes cfhl1 and five factor hrelated cfhr proteins. Complement has been shown to possess approximately 31 proteins.

A polymorphism in complement factor h cfh has been strongly associated with the disease, but the mechanism. Humans, but not all other mammals, produce a smaller protein, factor h like protein 1 fhl1, by alternative splicing of the factor h gene. The strain studied here is of the clinically important m1 serotype and expresses two structurally related surface proteins, the m1 protein and protein h. The acquisition of regulatory proteins is a means of bloodborne pathogens to avoid destruction by the human complement. Rnabinding proteins in human genetic disease kiven e. The factor h cfhr family comprises a group of highly related proteins that includes the five complement factor h related proteins, cfhr1, cfhr2, cfhr3, cfhr4, cfhr5, factor h and the spliced variant factor h like protein 1 fhl1. Complement factor h mutations and gene polymorphisms in. This cited by count includes citations to the following articles in scholar. Diseaseassociated mutants of these proteins with duplicated. Factor h family proteins and human diseases request pdf. Genetics and disease associations of human complement factor h clin. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium. Complement factor h and the hemolytic uremic syndrome.