UCSD MOLECULE PAGES Properdin Jun Min 1 , Anjana Chandrasekhar 1 , Ashok Reddy Dinasarapu 1 , Claudia Kemper 2 , Shankar Subramaniam 3 Review Article Open Access Properdin is currently the only known positive regulator of complement activation and stabilizes the alternative pathway C3 convertase (C3bBb). It is composed of multiple identical protein subunits, with each subunit carrying a separate ligand- binding site. Previous reports suggest that properdin function depends on multiple interactions between its subunits and its ligands. Properdin recognizes several pathogen- or damage/danger-associated molecular patterns (PAMPs and DAMPs, respectively) on foreign and apoptotic cells. Once bound, it initiates and propagates the complement response by attracting fluid-phage C3b to recognize surfaces and fostering de novo convertase assembly, and by stabilizing C3 convertase complexes (C3bBbfP). Therefore, it is central to continuous deposition of the activated complement fragment C3b on the surfaces of the pathogens, which it achieves by preventing the dissociation of the Bb catalytic subunit from the inherently labile C3bBb complexes. KEYWORDS BFD; CFP; Complement factor P; Complement factor properdin; PFC; PFD; Properdin; PROPERDIN; Properdin P factor, complement IDENTIFIERS Molecule Page ID:A004258, Species:Human, NCBI Gene ID: 5199, Protein Accession:NP_001138724.1, Gene Symbol:CFP PROTEIN FUNCTION Properdin is a positive regulator of the alternative pathway of the complement system, a system that is a key part of an innate immune system and that has been recently shown to be involved in many other processes including tissue regeneration (Markiewski et al . 2006), lipid metabolism (Ohinata and Yoshikawa 2008), adaptive immunity (Carroll 2004) and immune homeostasis (Ricklin et al. 2010). There are three major activation pathways in the complement system: the classical, the lectin, and the alternative pathway. All activation pathways lead to formation of C3/C5 convertases that can cleave the main complement proteins C3 and C5 to progress the downstream proteolytic complement cascade. Among the three activation pathways, the alternative pathway includes the amplification branch of the complement system that can account for up to 80-90% of total complement activation (Jelezarova and Lute 1999). One of the initiation mechanisms for the alternative pathway involves the use of properdin as a pattern-recognition molecule; properdin can recognize and bind to certain ligands on cell surfaces to initiate and propagate the complement response. The downstream response of the complement system is carried out by complement effector molecules such as C3b, the anaphylatoxins C3a, C5a, and the membrane attack complex (MAC), which mediate uptake/clearance of dangerous targets, local inflammation, chemotaxis, and cell lysis respectively (Ricklin and Lambris 2013). Properdin can initiate the assembly of the C3bBb complex, a highly efficient C3-cleaving enzyme in the alternative pathway of the complement system, by recruiting fluid-phase C3b or C3 convertase to cell surfaces for complement response and is essential in stabilizing formed C3 convertases. Through surface plasmon resonance technology, Hourcade (2006) has derived a model for properdin activity on target surfaces. In this model, properdin trimer binds to surface-bound C3b, which is then joined by factor B and cleaved by factor D, generating the C3 convertase, C3bBbP. This convertase cleaves another molecule of C3 to generate C3b that binds to the second binding site on properdin. The newly properdin-bound C3b is then joined by new factor B and factor D, generating C3bBb on the second binding site of properdin. This protein complex that is held together by properdin can assist in further C3 cleavage and downstream complement response. The study has also shown that properdin accelerates the association of C3b with factor B and provides a focal point for the assembly of C3 convertase on a target surface. A recent study, utilizing electron microscopy technique, has also suggested a similar model for properdin activity, in which properdin cross-links C3b and factor B, and also displaces the negative regulatory domain of C3b (TED) (Alcorlo et al . 2013). Another study has shown that the initiation and the assembly of C3bBb could start from properdin binding directly to specific target surfaces instead of properdin binding to C3b-bound surface, providing a bigger role for properdin, e.g., that of a 'DAMP recognizer', in the activation of the alternative pathway of the complement system (Spitzer et al. 2007). New context-dependent mechanisms of properdin- initiated alternative pathway activation are being researched. For example, properdin released by activated neutrophils can bind to activated platelets and initiate formations of P- C3(H2O),Bb or C3bBbP. The study also showed C3(H2O) initiating C3 convertase formation with properdin acting as stabilizer (Saggu et al. 2013). In addition to initiating and accelerating the assembly of C3bBb, properdin has been shown to stabilize C3bBb, normally a short-lived complex, by 5-10 fold (Fearon and Austen 1975). Furthermore, properdin stabilizes and increases the activity of the C3 convertase in patients with renal disease by increasing the activity of specific autoantibodies called C3 nephritic factors that bind to C3 convertases and prolong the half-life of the enzyme complex (Paixão-Cavalcante et al. 2012). Properdin recognizes a variety of microbial targets and dangerously altered-self cells to function as initiation point for the activation of alternative pathway of the complement system. A study has shown properdin could bind zymosan, Neisseria gonorrhoeae , lipopolysaccharide-defective E.coli and Salmonella typhimurium (Spitzer et al. 2007). Properdin has 1 Department of Bioengineering, University of California, San Diego, CA 92093, US. 2 MRC Centre for Transplantation, Department of Transplant Immunology and Mucosal Biology, King's College, London, SE1 9RT, UK. 3 Department of Bioengineering, University of California at San Diego, CA 92093, US. Correspondence should be addressed to Anjana Chandrasekhar: a4chandra@ucsd.edu Published online: 23 Jan 2014 | doi:10.6072/H0.MP.A004258.01 doi:10.6072/H0.MP.A004258.01 Volume 2, Issue 2, 2013 Copyright UC Press, All rights reserved. www.signaling-gateway.org