Structural studies offer a framework for understanding the role of properdin in the alternative pathway and beyond

Abstract

The complement cascade is activated when pattern recognition molecules recognize pathogens, dying host cells or immune complexes. The proteolytic cascades in complement can initiate through the classical pathway (CP) or the lectin pathway (LP) which leads to assembly of the CP/LP C3 convertase C4b2a. This proteolytic enzyme turns over complement C3 into the anaphylatoxin C3a and the opsonin C3b that may become covalently linked to the surface of the complement activator (Figure 1A). The downstream alternative pathway (AP) provides an amplification loop for the two other pathways. 1 The C3b initially deposited by the CP C3 convertase can associate with Factor B (FB) and form the AP proconvertase C3bB that upon cleavage by Factor D (FD) becomes the active AP C3 convertase C3bBb. 1 This initiates a positive feedback loop, which markedly amplifies the complement activation through the CP and LP. 2,3 FP is central in the AP amplification loop and binds directly to C3b, the C3bB proconvertase, and the C3bBb convertase (Figure 1A). The alternative pathway may also initiate in the

Decreased plasma cartilage acidic protein 1 in COVID‐19

“…In the global screen revealing an interaction between CFP and CRTAC1, the two proteins were in 293 cell lysates, and affinity‐tagged CRTAC1 served as a bait (Huttlin et al, 2021 ). Prior to secretion, CFP and CRTAC1 are processed in the endoplasmic reticulum and Golgi to undergo disulfide bonding and C‐linked mannosylation, O‐linked fucosyl glucosylation, and N‐linked glycosylation in the case of CFP and disulfide bonding and O‐linked glycosylation in the case of CRTAC1 (Pedersen et al, 2023 ; Steck et al, 2007 ). To exclude the possibility that the interaction detected in cell lysate (Huttlin et al, 2021 ) is an artifact of incomplete protein processing, we set up an interaction ELISA to test interactions between recombinant CRTAC1 and CFP purified after secretion from mammalian cells with the required processing machinery.…”

The complement alternative pathway in health and disease—activation or amplification?

“…In part, this is because of its propensity to self‐aggregate during isolation, aggregated properdin having properties that are not found in the native protein 10 . Pedersen and co‐workers present an elegant description of properdin function, largely drawn from structural insights, with novel data 11 . They also bring a structural focus to the interactions of properdin with pathogens and some of their complement‐evasion strategies.…”

“…10 Pedersen and co-workers present an elegant description of properdin function, largely drawn from structural insights, with novel data. 11 They also bring a structural focus to the interactions of properdin with pathogens and some of their complement-evasion strategies. The role of the unusual C-mannosyl glycosylation of tryptophan residues remains enigmatic however.…”

Properdin deficiency associated with systemic meningococcal disease due to a novel p.Cys337Arg pathogenic variant

“…Properdin (FP) is a soluble glycoprotein with a key role in the regulation of the alternative pathway (AP) of the complement system. 1 Neutrophils are the main source of FP, although monocytes, bone marrow progenitors, and T cells also synthesize this complement regulator. FP is codified by the gene CFP , located at Xp11.23–p11.3, and formed by 10 exons, of which exons 2 to 10 are translated conforming six thrombospondin type I repeats (TSR1-6).…”

“…FP is codified by the gene CFP , located at Xp11.23–p11.3, and formed by 10 exons, of which exons 2 to 10 are translated conforming six thrombospondin type I repeats (TSR1-6). 1 FP deficiency (MIM # 312060) is a rare X-linked disorder that contributes to increased susceptibility to infectious diseases, mainly caused by rare strains of Neisseria meningitidis such as serogroups W-135 and Y. Since its initial description in 1982, 2 more than 100 cases have been reported worldwide demonstrating susceptibility to meningococcal infections and sepsis.…”