CFP

Properdin (CFP) is the sole positive regulator of the alternative complement pathway, functioning both as a stabilizer of the C3bBb convertase and as a pattern-recognition molecule that initiates complement activation on target surfaces. Properdin cross-links the C345C domain of C3b and the vWA domain of Bb through its oligomeric vertices, displacing the TED/CUB domains to impair regulatory protein access and thereby prolonging convertase half-life (PMID:23901101, PMID:16301317). Stored in neutrophil secondary granules and released upon inflammatory stimulation, properdin binds apoptotic/necrotic cells via glycosaminoglycans and exposed DNA, activated platelets, and renal tubular epithelial cells independently of pre-existing C3b, recruiting C3b or C3(H2O) to assemble convertases de novo (PMID:9127010, PMID:18579773, PMID:18490764, PMID:23677468, PMID:18753294). Beyond complement, properdin directly engages the NK cell-activating receptor NKp46 to bridge alternative pathway activation with innate lymphoid cell defense against Neisseria meningitidis (PMID:28480349), and inherited properdin deficiency abolishes alternative pathway function while leaving the classical pathway intact (PMID:7151327).

1. 1982 High

   Properdin deficiency in a human family established that CFP is specifically and non-redundantly required for alternative pathway complement activation, resolving whether the alternative pathway could function without properdin.

   Evidence Hemolytic, opsonization, and alternative pathway activation assays in naturally properdin-deficient patient serum

   PMID:7151327

   Open questions at the time

   • Molecular mechanism of convertase stabilization unknown at this point
   • Whether properdin has functions beyond convertase stabilization not addressed
2. 1997 High

   Demonstration that properdin is stored in neutrophil secondary granules and released by inflammatory mediators identified a local, regulatable secretory source, answering how properdin reaches sites of infection.

   Evidence Percoll density gradient fractionation, Western blot, flow cytometry, and RT-PCR in human neutrophils

   PMID:9127010

   Open questions at the time

   • What surface ligands properdin recognizes on target cells unknown
   • Whether other cell types contribute significant properdin secretion not determined
3. 2000 High

   Mass spectrometric characterization revealed that 14 of 17 WXXW-motif tryptophans in properdin's thrombospondin type 1 repeats are fully C-mannosylated, establishing CFP as one of the most extensively C-mannosylated human proteins and raising questions about how this modification affects folding or function.

   Evidence Mass spectrometry and Edman degradation of purified properdin peptides

   PMID:10878002

   Open questions at the time

   • Functional consequences of C-mannosylation for properdin activity or oligomerization not determined
   • Whether C-mannosylation is required for secretion or ligand binding unknown
4. 2005 High

   Quantitative SPR binding studies showed that properdin binds both preformed C3bBb convertases and nascent C3b/C3b-factor B intermediates, establishing that properdin serves as a platform for de novo convertase assembly rather than merely stabilizing preformed complexes.

   Evidence Surface plasmon resonance with purified complement proteins

   PMID:16301317

   Open questions at the time

   • Structural basis of how properdin contacts both C3b and Bb simultaneously not resolved
   • Whether properdin-directed assembly occurs on physiological surfaces not shown
5. 2008 High

   Three independent studies demonstrated that properdin binds apoptotic/necrotic cells (via glycosaminoglycans and exposed DNA) and renal tubular epithelial cells independently of C3b, redefining properdin as a direct pattern-recognition molecule capable of initiating complement activation on target surfaces.

   Evidence Flow cytometry, complement deposition assays, GAG-competition experiments, properdin-deficient serum reconstitution, and kidney biopsy immunohistochemistry

   PMID:18490764 PMID:18579773 PMID:18753294

   Open questions at the time

   • Identity of the specific surface receptor/proteoglycan on tubular epithelial cells not determined
   • Relative in vivo contributions of C3b-dependent vs. C3b-independent properdin binding unclear
6. 2013 High

   Electron microscopy of properdin–C3bBb complexes revealed that oligomeric properdin vertices simultaneously contact the C345C domain of C3b and the vWA domain of Bb, while displacing the TED/CUB domains to impair regulatory cofactor access — providing the first structural mechanism for convertase stabilization. Concurrently, properdin was shown to recruit C3(H2O) to activated platelets to assemble a novel cell-bound C3(H2O),Bb convertase.

   Evidence Electron microscopy of properdin–convertase complexes; flow cytometry and complement deposition assays on activated platelets with properdin-deficient serum reconstitution

   PMID:23677468 PMID:23901101

   Open questions at the time

   • Atomic-resolution structure of the properdin–convertase interface not available
   • Physiological significance of the C3(H2O),Bb convertase on platelets in thromboinflammation not established in vivo
7. 2017 High

   Identification of properdin as a direct ligand for the NK cell receptor NKp46 revealed a complement-independent role for CFP in innate lymphoid cell activation, bridging humoral and cellular innate immunity during bacterial infection.

   Evidence Binding assays and in vivo survival experiments in NKp46-deficient and CFP-deficient mouse Neisseria meningitidis infection models

   PMID:28480349

   Open questions at the time

   • Binding interface between properdin and NKp46 not structurally defined
   • Whether properdin–NKp46 interaction is relevant to viral or tumor contexts unknown
8. 2019 Medium

   Overexpression studies revealed a tumor-suppressive role for CFP in breast cancer through TES-mediated upregulation of the ER-stress factor DDIT3, suggesting a complement-independent intracellular or paracrine function.

   Evidence Overexpression in MCF7 cells, in vitro growth assays, in vivo xenograft models, gene expression analysis

   PMID:30755730

   Open questions at the time

   • Mechanism by which a secreted complement protein induces intracellular DDIT3 via TES not resolved
   • Not independently replicated in other breast cancer models or cell lines
   • Whether the effect is direct (intracrine) or paracrine remains unclear

• Key open questions include the atomic-resolution structure of the properdin–C3bBb complex, the functional impact of extensive C-mannosylation on properdin activity, and whether the NKp46-binding and tumor-suppressive roles reflect independent or interconnected biological functions.
• No high-resolution crystal or cryo-EM structure of properdin in complex with C3bBb
• Functional consequence of C-mannosylation on properdin folding, secretion, or ligand binding untested
• Relationship between NKp46-mediated NK activation and complement effector functions not integrated