C2

Complement C2 is a serine protease that supplies the catalytic activity of the classical and lectin pathway C3 convertase, positioning it as a central node in antibody- and lectin-triggered complement activation (PMID:6149575, PMID:6149579, PMID:23410585). The cloned cDNA encodes a 732-residue secreted polypeptide whose recombinant product is antigenically and hemolytically indistinguishable from serum C2, confirming the gene is sufficient to specify the functional protein (PMID:2493504, PMID:3850903). C2 and Factor B are homologous proteases encoded by adjacent single-copy loci in the MHC class III region; the C2 catalytic chain carries the convertase active site while its non-catalytic chain is built from three complement-control-protein (Sushi) repeats (PMID:6149575, PMID:6149579, PMID:3902623). Assembly of the proconvertase requires C2 binding to C4b: the Sushi-2 domain mediates this interaction, and antibody (ARGX-117) blockade of Sushi-2 prevents proconvertase formation and abrogates classical and lectin — but not alternative — pathway activation upstream of C3 (PMID:32926878). The C2a segment is also the docking site exploited by the parasite inhibitor CRIT, which competes with C4b for C2 (PMID:11994478). C2 expression is regulated pretranslationally, being upregulated by IFN-γ in monocytes and transfected fibroblasts at the mRNA level without requiring new protein synthesis (PMID:2866182). C2 is a critical effector in complement-mediated tissue injury, since its in vivo knockdown reduces C3 and membrane-attack-complex deposition and disease severity in experimental myasthenia gravis (PMID:23410585), and a common 28-bp exon-6 deletion causes type I C2 deficiency that is enriched in SLE patients (PMID:7932427).

1. 1984 High

   Establishing that C2 carries the catalytic site of the classical pathway C3 convertase and is structurally a serine protease defined its core enzymatic role and its evolutionary kinship with Factor B.

   Evidence CNBr peptide amino acid sequencing and biochemical convertase characterization, plus genomic Southern blot and cosmid mapping of the MHC class III locus

   PMID:3902623 PMID:6149575 PMID:6149579

   Open questions at the time

   • Did not resolve the structural basis of C4b recognition
   • Catalytic mechanism on C3 substrate not detailed at residue level
2. 1985 High

   Demonstrating IFN-γ-driven, cycloheximide-independent increases in C2 synthesis showed the gene is controlled pretranslationally at the mRNA level, linking C2 production to immune activation signals.

   Evidence Metabolic labeling, mRNA quantification and cycloheximide block in primary monocytes and transfected L cells

   PMID:2866182 PMID:3850903

   Open questions at the time

   • Promoter/enhancer elements and transcription factors mediating IFN-γ response not identified
   • Did not distinguish transcriptional rate from mRNA stability effects
3. 1989 High

   Cloning the full-length cDNA and reconstituting a hemolytically active secreted protein confirmed that the single C2 transcript encodes the complete functional protease.

   Evidence cDNA cloning with COS cell expression, Western blot and hemolytic activity assay

   PMID:2493504

   Open questions at the time

   • No structural model of the mature protein
   • Post-translational cleavage to C2a/C2b not mechanistically dissected here
4. 1994 Medium

   Identifying the 28-bp exon-6 deletion as the most common cause of type I C2 deficiency and its enrichment in SLE connected C2 loss-of-function to autoimmune disease.

   Evidence PCR genotyping of the exon-6 deletion in SLE patients versus controls

   PMID:7932427

   Open questions at the time

   • Association is genetic/population-level, not a direct causal mechanism for SLE
   • HLA-DRB1*1501 linkage confounds attribution to C2 alone
5. 1999 High

   Showing that complement-mediated tissue damage can proceed via a C2-bypass requiring both classical and alternative pathways clarified the pathway dependencies around C2 in vivo.

   Evidence Forssman shock model in C2-deficient guinea pigs with pathway-specific inhibitors (sCR1, EGTA-Mg2+) and in vitro hemolysis

   PMID:10477630

   Open questions at the time

   • Molecular identity of the bypass convertase not defined
   • Relevance of the bypass to human C2 deficiency unresolved
6. 2002 Medium

   Mapping the parasite inhibitor CRIT to the C2a segment, where it competes with C4b, localized the C4b-binding interface and revealed a host-mimicry inhibition strategy.

   Evidence Hemolytic inhibition and peptide competition assays with antibody cross-reactivity

   PMID:11994478

   Open questions at the time

   • Structural detail of the CRIT/C4b shared epitope not solved
   • Physiological relevance to immune evasion in infection not established
7. 2013 Medium

   In vivo siRNA knockdown showing reduced complement deposition, preserved acetylcholine receptors and improved muscle strength established C2 as a tractable effector node in classical-pathway autoimmune pathology.

   Evidence In vivo siRNA knockdown in EAMG mice with mRNA, NMJ complement immunofluorescence and muscle strength readouts

   PMID:23410585

   Open questions at the time

   • Single-lab study
   • Did not separate liver-derived from local C2 contributions to pathology
8. 2020 High

   Defining the ARGX-117 epitope on the Sushi-2 domain pinpointed the C4b-binding region required for proconvertase assembly and validated upstream pathway-selective C2 inhibition.

   Evidence Antibody mode-of-action binding, in vitro cytotoxicity assays and PK/PD in cynomolgus monkeys

   PMID:32926878

   Open questions at the time

   • No high-resolution structure of the C2 Sushi-2/C4b complex
   • Lectin-pathway-specific contributions not separated from classical pathway in vivo

• The atomic structure of C2 bound to C4b and the residue-level mechanism of C3 substrate cleavage by the C4b2a convertase remain undefined in this corpus.
• No experimental structure of the proconvertase or active convertase
• Catalytic mechanism and substrate specificity determinants uncharacterized