Complement component C5 is a 1,676-residue secreted plasma glycoprotein of the alpha-2-macroglobulin/complement C3-C4-C5 family that circulates as a disulfide-linked two-chain precursor (beta chain residues 19-673 and alpha chain residues 678-1676) and serves as the central proteolytic bifurcation point of the terminal complement cascade. Cleavage of the alpha chain at Arg751-Leu752 by classical/lectin (C4b2a3b), alternative (C3bBb3b), or granzyme K-generated C5 convertases releases two functionally distinct effector products: the 74-residue C5a anaphylatoxin (residues 678-751) and the large C5b fragment (alpha' chain residues 752-1676 disulfide-linked to the beta chain). C5a is a four-helix bundle peptide ligand that directly binds and activates the seven-transmembrane G protein-coupled receptor C5aR1 (CD88) via a two-site mechanism (core H1-H3 bundle binding the receptor N-terminus and C-terminal Arg751 inserting into the transmembrane orthosteric pocket) to trigger Gi/o- and beta-arrestin-mediated signaling, leukocyte chemotaxis, degranulation, and acute inflammatory responses, while also engaging the non-G-protein-coupled seven-transmembrane receptor C5aR2 (C5L2/GPR77) to modulate beta-arrestin recruitment and receptor scavenging; plasma carboxypeptidases rapidly cleave Arg751 to generate C5a des-Arg (residues 678-750) with reduced C5aR1 potency. Concurrently, nascent C5b undergoes a conformational rearrangement of its MG-ring, CUB, and TED domains that exposes a labile binding site for C6, initiating sequential non-enzymatic assembly with C6, C7, C8, and polymeric C9 to form the cytolytic membrane attack complex (MAC, C5b-9).
Curated functional classes representing distinct biological activities. These may be splice variants, cleavage products, or other forms with different functions.
C5_C5APRO_0000005988 (residues 678-751) C5_C5BPRO_0000005989, PRO_0000005985 (residues 19-673,752-1676) | GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001664 G protein-coupled receptor binding | IEA GO_REF:0000117 | ACCEPT | Summary: Core molecular function of the C5a anaphylatoxin fragment, which directly binds and activates the G protein-coupled receptors C5aR1 and C5aR2. Reason: Cleavage of C5 at Arg751-Leu752 releases the 74-residue C5a anaphylatoxin (PRO_0000005988), which directly binds the orthosteric pocket and N-terminal sulfotyrosine domain of the G protein-coupled receptor C5aR1 (CD88) as well as the seven-transmembrane receptor C5aR2 (C5L2). High-resolution cryo-EM structures (PMID:36806352; PMID:37169960; PMID:37852260) and site-directed mutagenesis (PMID:8182049; PMID:9553099) define the direct two-site GPCR binding interface. Supporting Evidence: PMID:36806352 The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and Ξ²-arrestin signaling pathways. PMID:37169960 The complement receptors C3aR and C5aR1, whose signaling is selectively activated by anaphylatoxins C3a and C5a, are important regulators of both innate and adaptive immune responses. |
| GO:0004866 endopeptidase inhibitor activity | IEA GO_REF:0000002 | REMOVE | Summary: Over-propagated InterPro2GO electronic annotation from alpha-2-macroglobulin superfamily domains; C5 lacks a protease-trapping bait region and thioester bond and is not an endopeptidase inhibitor. Reason: This IEA annotation derives from InterPro2GO mappings on the shared alpha-2-macroglobulin family domains (IPR001599, IPR002890). Unlike alpha-2-macroglobulin (A2M), which traps and inhibits endopeptidases via a bait region and an internal reactive thioester bond, complement C5 lacks an internal thioester bond and functions as a substrate cleaved by C5 convertases to generate C5a and C5b (PMID:19528535; PMID:22832194). Supporting Evidence: PMID:22832194 C5 lacks the prototypical thioester present in this domain in other members of the C3/Ξ±2-macroglobulin protein family. |
| GO:0005102 signaling receptor binding | TAS PMID:10820279 Differential ability of exogenous chemotactic agents to disr... | MODIFY | Summary: True of the C5a cleavage product but too general; refine to GO:0001664 (G protein-coupled receptor binding). Reason: C5a acts as a signaling ligand by directly binding the seven-transmembrane receptors C5aR1 and C5aR2. Because C5 already carries the more specific descendant term GO:0001664 (G protein-coupled receptor binding), this broad parent term should be refined to GO:0001664. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:36806352 The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and Ξ²-arrestin signaling pathways. |
| GO:0005102 signaling receptor binding | TAS PMID:9590258 Expression of receptors for C5a anaphylatoxin (CD88) on huma... | MODIFY | Summary: True of the C5a cleavage product in PMID:9590258 but too general; refine to GO:0001664 (G protein-coupled receptor binding). Reason: PMID:9590258 examines C5a stimulation of the human C5a receptor (CD88/C5aR1), a G protein-coupled receptor, on human bronchial epithelial cells. Refine to the specific descendant term GO:0001664 (G protein-coupled receptor binding), which is already annotated to C5. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: PMID:9590258 Control (untreated) HBECs responded to C5a (50 nM) by releasing the proinflammatory cytokine IL-8 at low but significant levels. |
| GO:0005515 protein binding | IPI PMID:19528535 Factor H-related protein 1 (CFHR-1) inhibits complement C5 c... | REMOVE | Summary: Valid physical interaction of C5 and C5b6 with complement regulator CFHR1 (Q03591), but bare GO:0005515 (protein binding) is removed per repository policy. Reason: PMID:19528535 demonstrates that Factor H-related protein 1 (CFHR1, Q03591) binds to C5 and C5b6 to inhibit C5 convertase activity and terminal complex assembly. However, per repository policy, bare GO:0005515 (protein binding) is removed as an uninformative molecular function term. Supporting Evidence: PMID:19528535 Here we identify CFHR1 as a novel inhibitor of the complement pathway that blocks C5 convertase activity and interferes with C5b surface deposition and MAC formation. |
| GO:0005515 protein binding | IPI PMID:21217642 Substrate recognition by complement convertases revealed in ... | REMOVE | Summary: Binding of C5 to exogenous Naja kaouthia cobra venom factor (CVF, Q91132); remove bare GO:0005515 (protein binding) per policy. Reason: PMID:21217642 determines the crystal structure of human C5 in complex with the exogenous Naja kaouthia cobra venom factor (CVF, Q91132, a C3b homologue). Bare GO:0005515 (protein binding) is uninformative and is removed per repository policy. Supporting Evidence: PMID:21217642 We determined the crystal structures of the C3b homologue cobra venom factor (CVF) in complex with C5, and in complex with C5 and the inhibitor SSL7 at 4.3 Γ
resolution. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput yeast two-hybrid hit with intracellular transcription factor CREB3L1 (Q96BA8); remove uninformative bare GO:0005515. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput intracellular yeast two-hybrid screen (PMID:25416956) pairing secreted disulfide-rich complement C5 with ER/nuclear CREB3L1. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183) testing secreted complement C5 in an intracellular yeast assay. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput HuRI yeast two-hybrid screen hit; remove bare GO:0005515 per repository policy. Reason: Bare GO:0005515 (protein binding) is removed per repository policy; moreover, this row derives from a high-throughput yeast two-hybrid screen (PMID:32296183). |
| GO:0005576 extracellular region | EXP PMID:106884 Fifth component of human complement: purification from plasm... | ACCEPT | Summary: Complement C5 is purified directly from human blood plasma and functions in the extracellular region. Reason: PMID:106884 describes the purification of human complement C5 from plasma and characterization of its two-chain disulfide-linked polypeptide structure. C5 and its cleavage products C5a and C5b localize to the extracellular region. |
| GO:0005576 extracellular region | EXP PMID:690134 Primary structural analysis of the polypeptide portion of hu... | ACCEPT | Summary: Secreted complement component from human plasma cleaved into extracellular C5a and C5b. Reason: PMID:690134 determines the complete primary structure of the C5a anaphylatoxin liberated from human serum C5 in the extracellular region. Supporting Evidence: PMID:690134 The C5a molecule is one of two spasmogenic fragments (i.e. C3a and C5a) released from serum components C3 and C5 during complement activation. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Secreted extracellular complement protein. Reason: C5 is synthesized with an 18-residue signal peptide and secreted into the extracellular region (plasma and interstitial fluids), where it is cleaved into C5a and C5b. |
| GO:0005576 extracellular region | TAS PMID:9218605 TNF-alpha-mediated expression of the receptor for anaphylato... | ACCEPT | Summary: Secreted extracellular complement protein detected in cerebrospinal fluid. Reason: PMID:9218605 detects the secreted C5a ligand in the extracellular cerebrospinal fluid of human patients with infectious meningitis. Supporting Evidence: PMID:9218605 The finding of TNF-alpha-mediated C5aR expression on neurons in experimental Listeria meningitis and the detection of the ligand, C5a, in the cerebrospinal fluid of human patients with infectious meningitis present new directions in the investigation of the pathophysiologic sequelae leading to secondary brain damage. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-173680 | ACCEPT | Summary: Extracellular localization of C5 during C5 convertase activation. Reason: C5 is activated in the extracellular region by C5 convertases. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-173705 | ACCEPT | Summary: Extracellular localization of C5b during C6 binding. Reason: C5b binds C6 in the extracellular region to form C5b6. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-173709 | ACCEPT | Summary: Extracellular localization of C5b during C7 binding to C5b6. Reason: C7 binds C5b6 in the extracellular region. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-173720 | ACCEPT | Summary: Extracellular localization of C5b-7 during translocation to target membranes. Reason: C5b-7 forms in the extracellular region and associates with target membranes. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-173723 | ACCEPT | Summary: Extracellular localization during C8 binding to C5b-7. Reason: C8 binds C5b-7 from the extracellular fluid. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-173725 | ACCEPT | Summary: Extracellular localization during C9 recruitment to C5b-8. Reason: C9 is recruited to C5b-8 from the extracellular region. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2530429 | ACCEPT | Summary: Extracellular localization of soluble VTN:C5b-9 (sC5b-9) complexes. Reason: Soluble vitronectin-bound C5b-9 complexes circulate in the extracellular region. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2530445 | ACCEPT | Summary: Extracellular localization during CD59 regulation of MAC assembly. Reason: Terminal complement assembly and its inhibition by CD59 occur at the extracellular face of the membrane. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2530453 | ACCEPT | Summary: Extracellular localization during vitronectin binding to C5b-7. Reason: Vitronectin binds C5b-7 in the extracellular space. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-375395 | ACCEPT | Summary: Extracellular localization of C5a binding to C5aR1. Reason: Released C5a anaphylatoxin binds C5aR1 in the extracellular region. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-380073 | ACCEPT | Summary: Extracellular localization of C5a in the C5a-C5aR1-Gi signaling complex. Reason: C5a remains bound to the extracellular orthosteric pocket of C5aR1 during Gi activation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749454 | ACCEPT | Summary: Extracellular localization of C5a in the C5a:C5aR1 complex. Reason: C5a acts at the extracellular face of C5aR1. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-749456 | ACCEPT | Summary: Extracellular localization of C5a bound to Gi-coupled C5aR1. Reason: C5a acts in the extracellular region as the agonist of C5aR1. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8852580 | ACCEPT | Summary: Extracellular localization during clusterin binding to terminal complement complexes. Reason: Clusterin binds soluble terminal complement complexes containing C5b in the extracellular region. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8852716 | ACCEPT | Summary: Extracellular localization of C5 during proteolytic cleavage. Reason: Extracellular proteases cleave C5 in the extracellular region. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8852809 | ACCEPT | Summary: Extracellular localization of C5a during carboxypeptidase N/B2 cleavage to C5a des-Arg. Reason: Plasma carboxypeptidases cleave C5a to C5a des-Arg in the extracellular region. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-964811 | ACCEPT | Summary: Extracellular localization of C5a and C5a des-Arg binding to C5AR2. Reason: C5a and C5a des-Arg bind the extracellular face of C5AR2 (C5L2). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9691621 | ACCEPT | Summary: Extracellular localization of C5 in plasma. Reason: C5 circulates in the extracellular plasma compartment. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9957405 | ACCEPT | Summary: Extracellular localization of C5a in plasma. Reason: Released C5a anaphylatoxin acts in the extracellular region. |
| GO:0005579 membrane attack complex | IDA PMID:22832194 Assembly and regulation of the membrane attack complex based... | ACCEPT | Summary: Cleavage product C5b is the structural nucleation subunit of the membrane attack complex (MAC, C5b-9). Reason: PMID:22832194 resolves the crystal structure of C5b6 and the cryo-EM map of sC5b9, demonstrating that C5b forms a stable complex with C6 and nucleates assembly of the C5b-9 membrane attack complex pore. Supporting Evidence: PMID:22832194 Upon complement activation, C5 is cleaved into C5a and C5b by the C5 convertase. C6 then captures a labile binding site in C5b (half-life: 2 min) |
| GO:0006935 chemotaxis | IEA GO_REF:0000117 | ACCEPT | Summary: Core biological process of the C5a anaphylatoxin fragment, which directs chemotaxis of neutrophils, monocytes, and macrophages via C5aR1. Reason: C5a released by cleavage of C5 is one of the most potent physiological chemoattractants for myeloid leukocytes, directing transendothelial migration and chemotaxis through C5aR1 (PMID:10820279; PMID:8759757). Supporting Evidence: PMID:10820279 If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. |
| GO:0006935 chemotaxis | TAS PMID:10820279 Differential ability of exogenous chemotactic agents to disr... | ACCEPT | Summary: C5a acts as a potent neutrophil chemoattractant directing leukocyte migration. Reason: PMID:10820279 demonstrates that C5a acts as a potent soluble chemoattractant for human neutrophils under flow and static transendothelial migration conditions. Supporting Evidence: PMID:10820279 If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. |
| GO:0006954 inflammatory response | IEA GO_REF:0000120 | ACCEPT | Summary: Core effector role of C5 and its C5a anaphylatoxin fragment in acute and chronic inflammatory responses. Reason: Proteolytic cleavage of C5 releases C5a, a primary anaphylatoxin that triggers vascular permeability, leukocyte recruitment, degranulation, and pro-inflammatory cytokine production via C5aR1 (PMID:8759757; PMID:14566334; PMID:36806352). Supporting Evidence: PMID:8759757 Here we report that C3a and C5a are, in fact, potent chemotaxins for the human mast cell line HMC-1. |
| GO:0006954 inflammatory response | TAS PMID:8759757 C3a and C5a are chemotaxins for human mast cells and act thr... | ACCEPT | Summary: C5a anaphylatoxin mediates mast cell recruitment and acute inflammatory responses via a pertussis toxin-sensitive receptor pathway. Reason: PMID:8759757 establishes that C5a acts as a potent chemotaxin for human mast cells through its pertussis toxin-sensitive G protein-coupled receptor, driving acute inflammatory responses. Supporting Evidence: PMID:8759757 Here we report that C3a and C5a are, in fact, potent chemotaxins for the human mast cell line HMC-1. |
| GO:0006956 complement activation | IEA GO_REF:0000120 | ACCEPT | Summary: Central effector component of the complement cascade whose cleavage into C5a and C5b initiates terminal complement activation. Reason: C5 is the point of convergence where classical, lectin, alternative, and granzyme K pathways cleave C5 into C5a and C5b to initiate terminal complement activation and membrane attack complex assembly (PMID:19528535; PMID:22832194; PMID:39914456). Supporting Evidence: PMID:22832194 Upon complement activation, C5 is cleaved into C5a and C5b by the C5 convertase. C6 then captures a labile binding site in C5b (half-life: 2 min) |
| GO:0007166 cell surface receptor signaling pathway | TAS PMID:10820279 Differential ability of exogenous chemotactic agents to disr... | MODIFY | Summary: True of the C5a cleavage product but too general; refine to GO:0038178 (complement component C5a signaling pathway). Reason: C5a signals through the cell-surface seven-transmembrane receptors C5aR1 and C5aR2. Refine this broad parent term to the specific pathway term GO:0038178 (complement component C5a signaling pathway). Proposed replacements: complement component C5a signaling pathway Supporting Evidence: PMID:36806352 The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and Ξ²-arrestin signaling pathways. |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:8898085 In Xenopus oocytes the human C3a and C5a receptors elicit a ... | MODIFY | Summary: True of the C5a cleavage product in PMID:8898085 but too general; refine to GO:0038178 (complement component C5a signaling pathway). Reason: PMID:8898085 demonstrates that C5a activates the human C5a receptor (C5aR1), a G protein-coupled receptor, expressed in Xenopus oocytes. Refine this general parent term to the specific descendant pathway GO:0038178 (complement component C5a signaling pathway). Proposed replacements: complement component C5a signaling pathway Supporting Evidence: PMID:8898085 Oocytes expressing the anaphylatoxin C3a and C5a receptors responded to both agonists, in each case the response to the cognate ligand was substantially more robust than the response elicited by the other anaphylatoxin. |
| GO:0008009 chemokine activity | TAS PMID:10820279 Differential ability of exogenous chemotactic agents to disr... | REMOVE | Summary: Mis-annotation of the complement C5a anaphylatoxin as a chemokine; C5a is a chemoattractant GPCR ligand but is not a member of the cysteine-motif chemokine superfamily. Reason: PMID:10820279 compares the CXC chemokines IL-8, ENA-78, and GRO-alpha with non-chemokine chemoattractants fMLP and C5a. C5a is a 74-residue four-helix bundle cleavage product of complement C5 (PTHR11412:SF83), not a member of the chemokine superfamily (IPR001811), and does not bind chemokine receptors; its receptor binding is captured by GO:0001664 (G protein-coupled receptor binding). Note that UniProt also curated four IDA GO:0008009 rows on human C3 (P01024; PMID:342601, PMID:5778786, PMID:37169960, PMID:37852260, updated 2025-04-22) that seeded PAINT node PTN008967461 in PTHR11412 and should likewise be removed on C3. Supporting Evidence: PMID:10820279 If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. |
| GO:0010575 positive regulation of vascular endothelial growth factor production | IDA PMID:14566334 An animal model of age-related macular degeneration in senes... | KEEP AS NON CORE | Summary: Downstream C5aR1-mediated induction of VEGF production by retinal pigment epithelial cells; keep as non-core. Reason: PMID:14566334 and PMID:16452172 show that C5a stimulation induces vascular endothelial growth factor (VEGF) production by retinal pigment epithelial (RPE) cells in age-related macular degeneration and choroidal neovascularization models. Because VEGF induction is a downstream, cell-type-specific transcriptional consequence of C5aR1 signaling rather than a primary molecular function of C5, retain as non-core. Supporting Evidence: PMID:14566334 Impaired macrophage recruitment may allow accumulation of C5a and IgG, which induces vascular endothelial growth factor (VEGF) production by RPE, possibly mediating development of CNV. |
| GO:0010575 positive regulation of vascular endothelial growth factor production | IDA PMID:16452172 Drusen complement components C3a and C5a promote choroidal n... | KEEP AS NON CORE | Summary: Downstream C5aR1-mediated induction of VEGF expression in retinal pigment epithelial cells; keep as non-core. Reason: PMID:16452172 demonstrates that C5a induces VEGF expression in human retinal pigment epithelial cells in vitro and in mouse RPE/choroid in vivo. Retain as a valid downstream non-core process secondary to C5a-C5aR1 signaling. Supporting Evidence: PMID:16452172 Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. |
| GO:0010760 negative regulation of macrophage chemotaxis | IDA PMID:14566334 An animal model of age-related macular degeneration in senes... | KEEP AS NON CORE | Summary: Reflects altered choroidal macrophage recruitment in PMID:14566334; retain as non-core. Reason: PMID:14566334 examines C5a-induced RPE/choroidal CCL2 production and macrophage recruitment in senescent Ccl2- or Ccr2-deficient mice; retain as non-core relative to C5a's primary chemotactic role (GO:0006935). Supporting Evidence: PMID:14566334 RPE or choroidal endothelial production of Ccl-2 induced by complement C5a and IgG may mediate choroidal macrophage infiltration into aged wild-type choroids. |
| GO:0016477 cell migration | IEA GO_REF:0000117 | MODIFY | Summary: True of C5a but too general; refine to the specific descendant term GO:0006935 (chemotaxis) already carried by C5. Reason: C5a directs directional leukocyte chemotaxis (GO:0006935) and cell chemotaxis (GO:0060326) via C5aR1. Refine the broad parent term GO:0016477 (cell migration) to GO:0006935 (chemotaxis). Proposed replacements: chemotaxis Supporting Evidence: PMID:10820279 If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. |
| GO:0032722 positive regulation of chemokine production | IDA PMID:14566334 An animal model of age-related macular degeneration in senes... | KEEP AS NON CORE | Summary: Downstream C5aR1-mediated induction of CCL2 chemokine production in retinal pigment epithelial and choroidal endothelial cells; keep as non-core. Reason: PMID:14566334 demonstrates that C5a stimulates CCL2 (MCP-1) chemokine production by RPE and choroidal endothelial cells. Retain as a valid downstream non-core output of C5aR1 signaling. Supporting Evidence: PMID:14566334 RPE or choroidal endothelial production of Ccl-2 induced by complement C5a and IgG may mediate choroidal macrophage infiltration into aged wild-type choroids. |
| GO:0045766 positive regulation of angiogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer from mouse C5 reflecting C5a-promoted choroidal neovascularization; keep as non-core. Reason: Transferred from mouse C5 (P06684) based on experimental evidence that C5a promotes VEGF production and laser-induced choroidal neovascularization (PMID:16452172). Retain as a downstream tissue-level non-core process. Supporting Evidence: PMID:16452172 Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. |
| GO:0050920 regulation of chemotaxis | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: C5a regulates leukocyte chemotaxis via C5aR1 and C5aR2; retain as non-core alongside GO:0006935 (chemotaxis). Reason: C5a gradients both drive chemotaxis and regulate transendothelial migration in response to competing chemoattractants (PMID:10820279); retain as non-core as direct participation in chemotaxis (GO:0006935) is already accepted as core. Supporting Evidence: PMID:10820279 If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. |
| GO:0051707 response to other organism | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad organism-level defense process reflecting C5-dependent bacterial clearance and cytolysis; keep as non-core. Reason: Both C5a-C5aR1 signaling (PMID:37169960) and C5b-9 membrane attack complex assembly (PMID:22832194; PMID:30552328) mediate innate immune defense against bacterial pathogens, making this broad defense term true but non-core relative to complement activation and C5a signaling. Supporting Evidence: PMID:30552328 CryoEM reconstructions reveal plasticity of the MAC pore and demonstrate how C5b6 acts as a platform, directing assembly of a giant Ξ²-barrel whose structure is supported by a glycan scaffold. |
| GO:0060326 cell chemotaxis | IEA GO_REF:0000108 | ACCEPT | Summary: Core biological process of the C5a anaphylatoxin fragment, which directs chemotaxis of neutrophils, monocytes, mast cells, and macrophages. Reason: Although this GO_REF:0000108 inter-ontology inference was triggered by the erroneous GO:0008009 (chemokine activity) annotation, a review judges the biological claim about the gene rather than the evidence code: C5a is one of the principal physiological mediators of cell chemotaxis (GO:0060326) for neutrophils, monocytes, mast cells, and macrophages via C5aR1 (PMID:10820279; PMID:8759757). Supporting Evidence: PMID:10820279 If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. PMID:8759757 Here we report that C3a and C5a are, in fact, potent chemotaxins for the human mast cell line HMC-1. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected in urinary exosome mass spectrometry proteomics; keep as non-core. Reason: Identified in high-throughput LC-MS/MS proteomics of human urinary exosomes (PMID:19056867). Reflects association of abundant secreted complement proteins with extracellular vesicles rather than a primary site of action. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. Overall, the analysis identified 1132 proteins unambiguously |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Detected in expressed prostatic secretion urinary exosome proteomics; keep as non-core. Reason: Identified in shotgun proteomics of exosomes isolated from expressed prostatic secretions in urine (PMID:23533145). Retain as non-core. Supporting Evidence: PMID:23533145 Global GO enrichment analyses of these 127 proteins revealed that the most significant functional categories were related to inflammation: immune response (27 proteins), response to wounding (21 proteins), defense response (19 proteins), inflammatory response (14 proteins) and complement activation (7 proteins) (Figure 1B). |
| GO:0160257 complement activation, GZMK pathway | IDA PMID:39914456 Granzyme K activates the entire complement cascade. | ACCEPT | Summary: C5 is cleaved into C5a and C5b by granzyme K-assembled C5 convertases to drive terminal complement activation in the GZMK pathway. Reason: PMID:39914456 demonstrates that lymphocyte-derived granzyme K (GZMK) cleaves C2 and C4 to assemble active C3 and C5 convertases on cell surfaces, which cleave C5 into biologically active C5a and C5b to trigger C5aR1 signaling and C5b-9 MAC assembly. Supporting Evidence: PMID:39914456 The nascent C4b and C2b fragments form a C3 convertase that cleaves C3, enabling the assembly of a C5 convertase that cleaves C5. The resulting convertases generate all the effector molecules of the complement cascade: the anaphylatoxins C3a and C5a, the opsonins C4b and C3b, and the membrane attack complex. |
| GO:0038178 complement component C5a signaling pathway | IDA PMID:36806352 Mechanism of activation and biased signaling in complement r... | NEW | Summary: Processed C5a anaphylatoxin (residues 678-751 of C5) is the direct orthosteric peptide agonist that initiates the complement component C5a signaling pathway via C5aR1 and C5aR2. Reason: Human C5aR1 (P21730) and C5aR2 (Q9P296) are annotated to GO:0038178 (complement component C5a signaling pathway), defined as 'The series of molecular signals initiated by complement component C5a binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process.' However, human C5 (P01031), which encodes the C5a anaphylatoxin ligand (PRO_0000005988, residues 678-751), lacked this specific pathway annotation in GOA, carrying only broad parent terms GO:0007166 and GO:0007186. Cryo-EM structures of C5a-bound C5aR1-Gi and C5aR1-beta-arrestin1 complexes (PMID:36806352; PMID:37169960; PMID:37852260) and biochemical/mutagenesis studies (PMID:8182049; PMID:8898085) demonstrate that C5a directly engages C5aR1 via a two-site mechanism to trigger conformational rearrangement of TM6/TM7 and activate Gi and beta-arrestin signaling. Supporting Evidence: PMID:36806352 The complement fragment C5a is one of its important effector components and exerts diverse physiological functions through activation of the C5a receptor 1 (C5aR1) and associated downstream G protein and Ξ²-arrestin signaling pathways. PMID:37169960 The complement receptors C3aR and C5aR1, whose signaling is selectively activated by anaphylatoxins C3a and C5a, are important regulators of both innate and adaptive immune responses. PMID:37852260 The complement system is a critical part of our innate immune response, and the terminal products of this cascade, anaphylatoxins C3a and C5a, exert their physiological and pathophysiological responses primarily via two GPCRs, C3aR and C5aR1. PMID:8182049 The binding domain of the human C5a receptor consists of two distinct and physically separable subsites. One of these sites binds the C-terminal 8 amino acids of C5a and is as yet undefined, while the second site lies in the N terminus of the receptor and interacts with the core of C5a. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: How do the distinct intracellular conformations of C5aR2 (C5L2) bound to intact C5a versus C5a des-Arg selectively recruit beta-arrestin isoforms without engaging heterotrimeric Gi proteins, and how does C5aR1-C5aR2 heteromerization tune downstream pro- versus anti-inflammatory signaling in human myeloid cells?
Q: What is the quantitative contribution of convertase-independent C5 cleavage by lymphocyte granzyme K (GZMK) and coagulation/neutrophil proteases (thrombin, elastase) relative to canonical C4b2a3b/C3bBb3b convertases in chronic human tissue inflammation?
Experiment: Determine high-resolution cryo-EM structures of human C5aR2 (C5L2) in complex with intact C5a, C5a des-Arg, and beta-arrestin-1/2 to compare the orthosteric pocket and intracellular core architecture with Gi- and beta-arrestin-bound C5aR1 (PMID:36806352; PMID:37169960; PMID:37852260).
Hypothesis: Divergent residues in the DRY-like motif and intracellular loop 3 of C5aR2 occlude the Galpha_i C-terminal helix binding cleft while stabilizing a phosphorylated C-terminal tail conformation that supports high-affinity C5a and C5a des-Arg scavenging and beta-arrestin coupling.
Experiment: Perform quantitative mass-spectrometry cleavage-site profiling of C5 fragments in synovial fluid and bronchoalveolar lavage from patients with rheumatoid arthritis and severe asthma, paired with selective inhibition of GZMK versus canonical C3/C5 convertases.
Hypothesis: Convertase-assembled C5 cleavage at Arg751-Leu752 (initiated either via canonical C1s/MASP/CFB or via GZMK-cleaved C4b2a3b) accounts for the majority of bioactive intact C5a(678-751), whereas non-convertase proteases generate distinct N- or C-terminally truncated C5 fragments with altered C5aR1/C5aR2 agonist potency.
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)