Complement Factor P

Complement Factor P Introduction of Complement Factor P Complement Factor P (CFP), also known as properdin, is the only known positively charged (pI>9.5) regulator of complement system. Factor P is a 53-kDa monomer composed of 6 globular domains that are homologous to the thrombospondin type 1 repeat (TSR), labeled TSR 1-6. Consisted of 442 amino acid residues, factor P is 26 nm in length and 2.5 nm in diameter, meanwhile, each subunit harbors a single Nglycosylation site in TSR-6 and is C-mannosylated at 14 different tryptophans, making properdin one of the most highly mannosylated proteins known. Significantly, native factor P subunits form head-to-tail dimers, trimers, and tetramers that resemble rods, triangles, and squares, respectively. And different formations usually present the fixed ratio 22:52:28.

Fig.1 Structure of factor P. (Blatt, 2016)

Function of Complement Factor P Factor P is historically recognized as a stabilizing component of the alternative pathway convertases, the central enzymes of the complement cascade. However, weighty evidence has revealed that factor P can also bind to target cells, phagocyte

receptors, and serum regulators, providing a platform for convertase assembly and function, and promotes target phagocytosis.

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Direct Regulation of Alternative Pathway Activity Factor P can enhance alternative pathway activity via two ways: (1) acting as a positive regulator of pre-existing alternative pathway activity or (2) initiating new alternative pathway activity. Acting as a positive regulator, factor P can stabilize the C3 convertase (C3bBb) of the alternative pathway, increasing their activity five to ten-fold. Factor P acts as a pattern recognition molecule to bind selectively to specific surfaces upon which it recruits C3b or C3(H2O) to direct and trigger alternative pathway.

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Binding to Apoptotic T Cells to Promote Phagocytosis Factor P can bind early apoptotic T cells, which promotes their phagocytic uptake by macrophages and dendritic cells. Additionally, surface-bound factor P directed deposition of C3b activation fragments on apoptotic T cells to enhance complement activation.

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Binding to Microbial Pathogens Factor P is showed directly to bind Neisseria gonorrhoeae and the resulting bacteria:properdin complexes induce C3 deposition to the microbial surface, which is beneficial for activation of complement pathway. These observations may account for why properdin-deficient individuals are particularly sensitive to meningococcal disease.

Fig.2 Regulation of factor P in the alternative pathway. (Blatt, 2016)

Factor P and Disease Factor P has been invariably found to be critical for alternative pathway activation, so a number of disorders mediated by the alternative pathway have close relevance with factor P. Indeed, apart from N. meningitidesinfection in P-deficient individuals, some autoimmune disease, most notably the development of systemic lupus erythematosus (SLE) and renal diseases are also associated with factor P. So, factor P may represent a promising therapeutic target in clinical.

Reference 1. Blatt, A. Z.; et al. Properdin: a tightly regulated critical inflammatory modulator. Immunological reviews. 2016, 274(1): 172-190. •