Menu
Home
People
Places
Arts
History
Plants & Animals
Science
Life & Culture
Technology
Reference.org
Complement component 5a
open-in-new
<h2 id="structure">Structure</h2> <p>Human polypeptide C5a contains 74 amino acids and has 11kDa. NMR spectroscopy proved that the molecule is composed of four helices and connected by peptide loops with three disulphide bonds between helix IV and II, III. There is a short 1.5 turn helix on <a href="/facts/N-terminus/yKYpuaBJ">N-terminus</a> but all agonist activity take place in the <a href="/facts/C-terminus/ws4scHgT">C-terminus</a>. C5a is rapidly metabolised by a serum enzyme <a href="/facts/Carboxypeptidase_B/pKou1q96">carboxypeptidase B</a> to a 72 amino acid form C5a des-Arg without C terminal arginine.<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a><a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> </p> <h2 id="functions">Functions</h2> <p>C5a is an <a href="/facts/Anaphylatoxin/PA6yC4Ne">anaphylatoxin</a>, causing increased expression of adhesion molecules on endothelium, contraction of smooth muscle, and increased vascular permeability. C5a des-Arg is a much less potent anaphylatoxin. Both C5a and C5a des-Arg can trigger <a href="/facts/Mast_cell/szfXss5q">mast cell</a> degranulation, releasing proinflammatory molecules <a href="/facts/Histamine/Vfjda665">histamine</a> and <a href="/facts/TNF-%25CE%25B1/7NWNIaCb">TNF-α</a>. C5a is also an effective <a href="/facts/Chemotaxis/hYPRdPTk">chemoattractant</a>,<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> initiating accumulation of complement and phagocytic cells at sites of infection or recruitment of antigen-presenting cells to lymph nodes.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> C5a plays a key role in increasing migration and adherence of neutrophils and monocytes to vessel walls. White blood cells are activated by upregulation of <a href="/facts/Integrin/DNYUGbBp">integrin</a> <a href="/facts/Avidity/zrA1tXeI">avidity</a>, the <a href="/facts/Prostaglandin/kIKw0gDj">lipoxygenase pathway</a> and <a href="/facts/Arachidonic_acid/7fMTra6z">arachidonic acid</a> metabolism. C5a also modulates the balance between activating versus inhibitory <a href="/facts/Immunoglobulin_G/cKzc83tk">IgG</a> <a href="/facts/Fc_receptor/hpv5q6Hu">Fc receptors</a> on leukocytes, thereby enhancing the <a href="/facts/Autoimmunity/5cASmcfI">autoimmune</a> response.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p> <h2 id="binding-process">Binding process</h2> <p>C5a interact with <a href="/facts/Receptor_(biochemistry)/tjTAC76a">receptor</a> protein C5a Receptor 1 (<a href="/facts/C5a_receptor/YM83g3TT">C5aR1</a>) on the surface of target cells such as macrophages, neutrophils and endothelial cells. C5aR1 is a member of the <a href="/facts/G-protein-coupled_receptor/0arUMkQc">G-protein-coupled receptor</a> superfamily of proteins, predicted to have seven transmembrane helical domains of largely hydrophobic <a href="/facts/Amino_acid/WDxYwBny">amino acid</a> residues, forming three intra- and three extra-cellular loops, with an extracellular N-terminus and an intracellular C-terminus. </p><p>C5a binding to the receptor is a two-stage process: an interaction between basic residues in the helical core of C5a and acidic residues in the extracellular N-terminal domain allows the C-terminus of C5a to bind to residues in the receptor transmembrane domains. The latter interaction leads to receptor activation, and the transduction of the ligand binding signal across the cell <a href="/facts/Plasma_membrane/vAXSD0DT">plasma membrane</a> to the cytoplasmic G protein <a href="/facts/Gi_alpha_subunit/ua0jmvM5">Gi</a> type <a href="/facts/GNAI2/rY6AWjdq">GNAI2</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Sensitivity of C5aR1 to C5a stimulation is enhanced by lipopolysaccharides exposure. C5a, acting via C5aR1, is shown to differentially modulate lipopolysaccharides-induced inflammatory responses in primary human monocytes versus macrophages,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> yet this is not due to C5aR1 upregulation.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> C5L2 is another C5a receptor that is thought to regulate the C5a-C5aR1 effects. There is apparently contradictory evidence showing decoy receptor activity conferring anti-inflammatory properties and also signalling activity conferring pro-inflammatory properties.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h2 id="diseases">Diseases</h2> <p>C5a is a powerful inflammatory mediator, and seems to be a key factor in the development of pathology of many inflammatory diseases involving the complement system such as sepsis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythemotosis, psoriasis. The inhibitor of C5a that can block its effects would be helpful in medical applications. Another candidate is PMX53 or PMX205 that is highly specific for CD88 and effectively reduces inflammatory response.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> C5a has been identified as a key mediator of <a href="/facts/Neutrophil/KL6oTt8b">neutrophil</a> dysfunction in <a href="/facts/Sepsis/n52bkffJ">sepsis</a>, with antibody blockade of C5a improving outcomes in experimental models.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> This has also been shown in humans,<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> with C5a-mediated neutrophil dysfunction predicting subsequent nosocomial infection<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> and death from sepsis.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> Recent data demonstrates that C5a not only impairs phagocytosis by neutrophils but also impairs phagosomal maturation,<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> inducing a marked alteration in the neutrophil phosphoproteomic response to bacterial targets. C5a binding to <a href="/facts/C5a_receptor/YM83g3TT">C5aR1</a> and C5aR2 (<a href="/facts/C5L2/7ngEr9Ru">C5L2</a>) mediates the formation of neutrophil extracellular traps and release of cytotoxic histones to the extracellular space, which is believed to act as a pathogenetic process of acute respiratory distress syndrome (<a href="/facts/ARDS/1V3mxJkU">ARDS</a>)<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> and promote tumor growth and metastasis.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=Complement+C5a">Complement+C5a</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Manthey HD, Woodruff TM, Taylor SM, Monk PN (November 2009). "Complement component 5a (C5a)". The International Journal of Biochemistry & Cell Biology. 41 (11): 2114–2117. doi:10.1016/j.biocel.2009.04.005. PMID 19464229. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Klos A, Wende E, Wareham KJ, Monk PN (January 2013). "International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors". Pharmacological Reviews. 65 (1): 500–543. doi:10.1124/pr.111.005223. PMID 23383423. <a href="https://doi.org/10.1124%2Fpr.111.005223" target="_blank">https://doi.org/10.1124%2Fpr.111.005223</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Ward PA (February 2004). "The dark side of C5a in sepsis". Nature Reviews. Immunology. 4 (2): 133–142. doi:10.1038/nri1269. PMID 15040586. S2CID 22630287. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Seow V, Lim J, Cotterell AJ, Yau MK, Xu W, Lohman RJ, et al. (April 2016). "Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists". Scientific Reports. 6 (1): 24575. Bibcode:2016NatSR...624575S. doi:10.1038/srep24575. PMC 4837355. PMID 27094554. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837355" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837355</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Gerard NP, Gerard C (February 1991). "The chemotactic receptor for human C5a anaphylatoxin". Nature. 349 (6310): 614–617. Bibcode:1991Natur.349..614G. doi:10.1038/349614a0. PMID 1847994. S2CID 4338594. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Manthey HD, Woodruff TM, Taylor SM, Monk PN (November 2009). "Complement component 5a (C5a)". The International Journal of Biochemistry & Cell Biology. 41 (11): 2114–2117. doi:10.1016/j.biocel.2009.04.005. PMID 19464229. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Fujita T (14 October 1999). Boulay F (ed.). "PROW and IWHLDA present the GUIDE on: CD88". Protein Reviews on the Web. Archived from the original on 2008-07-24. <a href="https://web.archive.org/web/20080724181852/http://mpr.nci.nih.gov/prow/guide/666919736_g.htm" target="_blank">https://web.archive.org/web/20080724181852/http://mpr.nci.nih.gov/prow/guide/666919736_g.htm</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Seow V, Lim J, Iyer A, Suen JY, Ariffin JK, Hohenhaus DM, et al. (October 2013). "Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a". Journal of Immunology. 191 (8): 4308–4316. doi:10.4049/jimmunol.1301355. PMID 24043889. S2CID 207429042. <a href="https://doi.org/10.4049%2Fjimmunol.1301355" target="_blank">https://doi.org/10.4049%2Fjimmunol.1301355</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Raby AC, Holst B, Davies J, Colmont C, Laumonnier Y, Coles B, et al. (September 2011). "TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2". European Journal of Immunology. 41 (9): 2741–2752. doi:10.1002/eji.201041350. PMC 3638321. PMID 21630250. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638321" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638321</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Klos A, Wende E, Wareham KJ, Monk PN (January 2013). "International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors". Pharmacological Reviews. 65 (1): 500–543. doi:10.1124/pr.111.005223. PMID 23383423. <a href="https://doi.org/10.1124%2Fpr.111.005223" target="_blank">https://doi.org/10.1124%2Fpr.111.005223</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Manthey HD, Woodruff TM, Taylor SM, Monk PN (November 2009). "Complement component 5a (C5a)". The International Journal of Biochemistry & Cell Biology. 41 (11): 2114–2117. doi:10.1016/j.biocel.2009.04.005. PMID 19464229. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Woodruff TM, Crane JW, Proctor LM, Buller KM, Shek AB, de Vos K, et al. (July 2006). "Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration". FASEB Journal. 20 (9): 1407–1417. doi:10.1096/fj.05-5814com. PMID 16816116. S2CID 9206660. <a href="https://doi.org/10.1096%2Ffj.05-5814com" target="_blank">https://doi.org/10.1096%2Ffj.05-5814com</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Jain U, Woodruff TM, Stadnyk AW (January 2013). "The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10". British Journal of Pharmacology. 168 (2): 488–501. doi:10.1111/j.1476-5381.2012.02183.x. PMC 3572573. PMID 22924972. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572573" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572573</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Huber-Lang MS, Younkin EM, Sarma JV, McGuire SR, Lu KT, Guo RF, et al. (September 2002). "Complement-induced impairment of innate immunity during sepsis". Journal of Immunology. 169 (6): 3223–3231. doi:10.4049/jimmunol.169.6.3223. PMID 12218141. <a href="https://doi.org/10.4049%2Fjimmunol.169.6.3223" target="_blank">https://doi.org/10.4049%2Fjimmunol.169.6.3223</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Conway Morris A, Kefala K, Wilkinson TS, Dhaliwal K, Farrell L, Walsh T, et al. (July 2009). "C5a mediates peripheral blood neutrophil dysfunction in critically ill patients". American Journal of Respiratory and Critical Care Medicine. 180 (1): 19–28. doi:10.1164/rccm.200812-1928OC. PMC 2948533. PMID 19324972. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948533" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948533</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Morris AC, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, McCulloch C, et al. (May 2011). "C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients". Blood. 117 (19): 5178–5188. doi:10.1182/blood-2010-08-304667. PMID 21292772. <a href="https://doi.org/10.1182%2Fblood-2010-08-304667" target="_blank">https://doi.org/10.1182%2Fblood-2010-08-304667</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Conway Morris A, Datta D, Shankar-Hari M, Stephen J, Weir CJ, Rennie J, et al. (May 2018). "Cell-surface signatures of immune dysfunction risk-stratify critically ill patients: INFECT study". Intensive Care Medicine. 44 (5): 627–635. doi:10.1007/s00134-018-5247-0. PMC 6006236. PMID 29915941. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006236" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006236</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Conway Morris A, Anderson N, Brittan M, Wilkinson TS, McAuley DF, Antonelli J, et al. (November 2013). "Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients". British Journal of Anaesthesia. 111 (5): 778–787. doi:10.1093/bja/aet205. PMID 23756248. <a href="https://doi.org/10.1093%2Fbja%2Faet205" target="_blank">https://doi.org/10.1093%2Fbja%2Faet205</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Unnewehr H, Rittirsch D, Sarma JV, Zetoune F, Flierl MA, Perl M, et al. (April 2013). "Changes and regulation of the C5a receptor on neutrophils during septic shock in humans". Journal of Immunology. 190 (8): 4215–4225. doi:10.4049/jimmunol.1200534. PMID 23479227. <a href="https://doi.org/10.4049%2Fjimmunol.1200534" target="_blank">https://doi.org/10.4049%2Fjimmunol.1200534</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Wood AJ, Vassallo AM, Ruchaud-Sparagano MH, Scott J, Zinnato C, Gonzalez-Tejedo C, et al. (August 2020). "C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling". JCI Insight. 5 (15). doi:10.1172/jci.insight.137029. PMC 7455072. PMID 32634128. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455072" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455072</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Bosmann M, Grailer JJ, Ruemmler R, Russkamp NF, Zetoune FS, Sarma JV, et al. (December 2013). "Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury". FASEB Journal. 27 (12): 5010–5021. doi:10.1096/fj.13-236380. PMC 3834784. PMID 23982144. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834784" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834784</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Ortiz-Espinosa S, Morales X, Senent Y, Alignani D, Tavira B, Macaya I, et al. (March 2022). "Complement C5a induces the formation of neutrophil extracellular traps by myeloid-derived suppressor cells to promote metastasis". Cancer Letters. 529: 70–84. doi:10.1016/j.canlet.2021.12.027. PMID 34971753. S2CID 245556050. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> </ol>