title: Functional anatomy of complement factor H.
abstract: Factor H (FH) is a soluble regulator of the proteolytic cascade at the core of the evolutionarily ancient vertebrate complement system. Although FH consists of a single chain of similar protein modules, it has a demanding job description. Its chief role is to prevent complement-mediated injury to healthy host cells and tissues. This entails recognition of molecular patterns on host surfaces combined with control of one of nature's most dangerous examples of a positive-feedback loop. In this way, FH modulates, where and when needed, an amplification process that otherwise exponentially escalates the production of the pro-inflammatory, pro-phagocytic, and pro-cytolytic cleavage products of complement proteins C3 and C5. Mutations and single-nucleotide polymorphisms in the FH gene and autoantibodies against FH predispose individuals to diseases, including age-related macular degeneration, dense-deposit disease, and atypical hemolytic uremic syndrome. Moreover, deletions or variations of genes for FH-related proteins also influence the risk of disease. Numerous pathogens hijack FH and use it for self-defense. As reviewed herein, a molecular understanding of FH function is emerging. While its functional oligomeric status remains uncertain, progress has been achieved in characterizing its three-dimensional architecture and, to a lesser extent, its intermodular flexibility. Models are proposed, based on the reconciliation of older data with a wealth of recent evidence, in which a latent circulating form of FH is activated by its principal target, C3b tethered to a self-surface. Such models suggest hypotheses linking sequence variations to pathophysiology, but improved, more quantitative, functional assays and rigorous data analysis are required to test these ideas.
authors.affiliation: School of Chemistry, University of Edinburgh, Edinburgh EH9 3JJ, U.K.
authors.forename: Elisavet
authors.initials: E
authors.lastname: Makou
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Herbert
authors.forename: Paul N
authors.initials: PN
authors.lastname: Barlow
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D003167:Complement Activation; D003179:Complement C3b / Q000737:chemistry / Q000502:physiology; D017242:Complement Factor H / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs
chemical_list: D003179:Complement C3b; D017242:Complement Factor H