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Complement component 3
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<h2 id="function">Function</h2> <p>C3 plays a central role in the activation of the <a href="/facts/Complement_system/vRSrQDUv">complement system</a>.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> Its activation is required for both <a href="/facts/Complement_system/vRSrQDUv">classical</a> and <a href="/facts/Alternative_complement_pathway/eN5PARpC">alternative complement activation</a> pathways. People with C3 deficiency are susceptible to bacterial infection.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> </p><p>One form of <a href="/facts/C3-convertase/yCSPm074">C3-convertase</a>, also known as C4b2b (formally known as C4b2a), is formed by a heterodimer of activated forms of C4 and C2.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> It catalyzes the <a href="/facts/Proteolytic/GtQdv6J7">proteolytic</a> cleavage of C3 into <a href="/facts/C3a_(complement)/RsklWBGY">C3a</a> and <a href="/facts/C3b/gQ2bfe0R">C3b</a>, generated during activation through the classical pathway as well as the <a href="/facts/Lectin_pathway/bRNAdBVe">lectin pathway</a>. C3a is an <a href="/facts/Anaphylotoxin/PA6yC4Ne">anaphylotoxin</a> and the precursor of some cytokines such as <a href="/facts/Acylation_stimulating_protein/fkLGqNjp">ASP</a>, and C3b serves as an <a href="/facts/Opsonin/wKPBjS1t">opsonizing</a> agent. <a href="/facts/Complement_factor_I/V9lHyyRn">Factor I</a> can cleave C3b into C3c and C3d, the latter of which plays a role in enhancing <a href="/facts/B_cell/6Y1tgwwp">B cell</a> responses. In the alternative complement pathway, C3 is cleaved by C3bBb, another form of C3-convertase composed of activated forms of C3 (C3b) and <a href="/facts/Factor_B/SVCLByyj">factor B</a> (Bb). Once C3 is activated to C3b, it exposes a reactive <a href="/facts/Thioester/UwfKqs1F">thioester</a> that allows the peptide to covalently attach to any surface that can provide a <a href="/facts/Nucleophile/xYccoaJQ">nucleophile</a> such as a primary amine or a hydroxyl group. Activated C3 can then interact with factor B. Factor B is then activated by factor D, to form Bb. The resultant complex, C3bBb, is called the alternative pathway (AP) C3 convertase. </p><p>C3bBb is deactivated in steps. First, the proteolytic component of the convertase, Bb, is removed by complement regulatory proteins having <a href="/facts/Decay-accelerating_factor/E93AKvrn">decay-accelerating factor</a> (DAF) activity. Next, C3b is broken down progressively to first iC3b, then C3c + C3dg, and then finally C3d. Factor I is the protease cleaves C3b but requires a <a href="/facts/Cofactor_(biochemistry)/AGo0PCUU">cofactor</a> (e.g <a href="/facts/Factor_H/YCE9FILF">Factor H</a>, CR1, MCP or C4BP) for activity. </p> <h2 id="structure">Structure</h2> <p>Several crystallographic structures of C3 have been determined<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> and reveal that this protein contains 13 domains.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a><a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><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> The <a href="https://www.uniprot.org/uniprot/P01024">C3 precursor protein</a> is first processed by the removal of 4 Arginine residues, forming two chains, beta and alpha, linked by a disulfide bond. The C3 convertase activates C3 by cleaving the alpha chain, releasing C3a anaphylatoxin and generating C3b (beta chain + alpha' (alpha prime) chain). </p> <h2 id="biochemistry">Biochemistry</h2> <h3>Biosynthesis</h3> <p>In humans, C3 is predominantly synthesised by liver <a href="/facts/Hepatocyte/USpvDz1n">hepatocytes</a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> and to some degree by epidermis <a href="/facts/Keratinocyte/drqhJjuS">keratinocytes</a>.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p> <h2 id="clinical-use">Clinical use</h2> <a href="/facts/Complement_system/vRSrQDUv">Complement</a> tests<table><tbody><tr><th><a href="/facts/Complement_component_4/nqX5xhav">C4</a> (<a href="/facts/Classical_complement_pathway/wtB1DPJn">C</a>)</th><th><a href="/facts/Complement_factor_B/SVCLByyj">FB</a> (<a href="/facts/Alternative_complement_pathway/eN5PARpC">A</a>)</th><th>C3</th><th><a href="/facts/Total_complement_activity/yjoFT1xl">CH50</a></th><th>Conditions</th></tr><tr><td>·</td><td>↓</td><td>↓</td><td>↓</td><td><a href="/facts/Poststreptococcal_glomerulonephritis/Vv3epgqz">PSG</a>, C3 NeF <a href="/facts/Autoantibody/gkMT0XyQ">AA</a></td></tr><tr><td>↓</td><td>·</td><td>↓</td><td>·</td><td><a href="/facts/Hereditary_angioedema/6JqCfLsn">HAE</a>, <a href="/facts/Complement_4_deficiency/gBlr015x">C4D</a></td></tr><tr><td>·</td><td>·</td><td>·</td><td>↓</td><td><a href="/facts/Terminal_complement_pathway_deficiency/LjDoEBcf">TCPD</a></td></tr><tr><td>↓</td><td>·/↓</td><td>↓</td><td>↓</td><td><a href="/facts/Systemic_lupus_erythematosus/kfHYawre">SLE</a></td></tr><tr><td>↑</td><td>↑</td><td>↑</td><td>↑</td><td><a href="/facts/Inflammation/Ura86MIy">inflammation</a></td></tr></tbody></table> <p>Levels of C3 in the <a href="/facts/Blood/03zEulkj">blood</a> may be measured to support or refute a particular medical diagnosis. For example, low C3 levels are associated with Systemic Lupus Erythematosus (SLE)<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> and some types of kidney disease such as <a href="/facts/Post-infectious_glomerulonephritis/Vv3epgqz">post-infectious glomerulonephritis</a>, <a href="/facts/Membranoproliferative_glomerulonephritis/v7lh4PFE">membranoproliferative glomerulonephritis</a>, and <a href="/facts/Shunt_nephritis/UjFtJmLT">shunt nephritis</a>. </p> <h2 id="regulation">Regulation</h2> <p><a href="/facts/Factor_H/YCE9FILF">Factor H</a> is the primary <a href="/facts/Regulator_gene/oH86M9nI">regulator</a> of C3. Deficiency of Factor H may lead to uncontrolled C3 activity through the <a href="/facts/Alternative_complement_pathway/eN5PARpC">alternative pathway</a> of the complement system.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h2 id="pathology">Pathology</h2> <p>Deficiency of C3 results in the affected person being <a href="/facts/Immunodeficiency/CIEujXmc">immunocompromised</a>. Specifically, they are vulnerable to bacterial pathogens, including repeat infections by the same organism, but are not susceptible to viruses. This vulnerability also occurs in an individual deficient in C1, <a href="/facts/Complement_component_2/IYmnHlH7">C2</a>, <a href="/facts/Complement_component_4/nqX5xhav">C4</a>, or any of their required components or associated proteins, and the clinical effects are very similar regardless of the specific deficiency. This is because all of these must work with C3 for the complement system to function.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>Affected people are particularly vulnerable to infections with Gram-negative organisms such as pathogenic <i><a href="/facts/Escherichia_coli/nR4Gvl56">E. coli</a></i> or <i><a href="/facts/Salmonella_enterica/uPm6xd3P">Salmonella enterica</a></i>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Additionally, C3 and other complement deficiencies are associated with frequent and severe <a href="/facts/Respiratory_tract_infection/lLKXWrJf">respiratory infections</a>, as well as other infections that invade and penetrate tissue layers.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>Some data shows that <a href="/facts/Acquired_characteristic/NqyYlBLC">acquired</a> C3 deficiency, including when this is intentionally done for medical <a href="/facts/Immunosuppressive_drug/ctlB3Hda">immunosuppression</a> purposes, may not significantly impact a person's immune function long-term.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> However, by contrast, <a href="/facts/Birth_defect/ESfzQhTx">congenital</a> C3 deficiency is known to cause chronic illness.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p><p>Additionally, several forms of C3 deficiency contribute to the development of <a href="/facts/Lupus/kfHYawre">systemic lupus erythematosus</a> and other <a href="/facts/Autoimmune_disease/sojBeQ7t">autoimmune diseases</a>.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Bradley DT, Zipfel PF, Hughes AE (Jun 2011). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178140">"Complement in age-related macular degeneration: a focus on function"</a>. <i>Eye</i>. 25 (6): 683–93. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1038%2Feye.2011.37">10.1038/eye.2011.37</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178140">3178140</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/21394116">21394116</a>.</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://www.ncbi.nlm.nih.gov/books/NBK1367/">GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/omim/277400,120700,120920,134370,134371,138470,188040,217030,235400,605336,605337,612922,612923,612924,612925,612926,120700,120920,134370,134371,138470,188040,217030,235400,605336,605337,612922,612923,612924,612925,612926">OMIM entries on Atypical Hemolytic-Uremic Syndrome</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/books/NBK1425/">GeneReviews/NCBI/NIH/UW entry on Dense Deposit Disease/Membranoproliferative Glomerulonephritis Type II</a></li> <li><a href="https://meshb.nlm.nih.gov/record/ui?name=Complement+C3">Complement+C3</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li> <li>Overview of all the structural information available in the <a href="/facts/Protein_Data_Bank/oUhq4ABD">PDB</a> for <a href="/facts/UniProt/lfDDHjAl">UniProt</a>: <i><a href="https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P01024">P01024</a></i> (Complement C3) at the <a href="/facts/PDBe-KB/p1WX7lPH">PDBe-KB</a>.</li></ul> <p><i>This article incorporates text from the <a href="/facts/United_States_National_Library_of_Medicine/Hzty0MCX">United States National Library of Medicine</a>, which is in the <a href="/facts/Public_domain/YWKMDKw4">public domain</a>.</i> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>de Bruijn MH, Fey GH (Feb 1985). "Human complement component C3: cDNA coding sequence and derived primary structure". Proceedings of the National Academy of Sciences of the United States of America. 82 (3): 708–12. Bibcode:1985PNAS...82..708D. doi:10.1073/pnas.82.3.708. PMC 397115. PMID 2579379. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397115" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC397115</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>"Entrez Gene: C3 complement component 3". <a href="https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=718" target="_blank">https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=718</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Sahu A, Lambris JD (Apr 2001). "Structure and biology of complement protein C3, a connecting link between innate and acquired immunity". 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Clinical and Experimental Immunology. 176 (1): 84–92. doi:10.1111/cei.12244. ISSN 0009-9104. PMC 3958157. PMID 24279761. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958157" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958157</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Fischer, Alain (2022). "Chapter 351: Primary Immune Deficiency Diseases". Harrison's Principles of Internal Medicine (21st ed.). New York: McGraw Hill. ISBN 978-1-264-26850-4. <a href="978-1-264-26850-4" target="_blank">978-1-264-26850-4</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Lappegård, Knut Tore; Christiansen, Dorte; Pharo, Anne; Thorgersen, Ebbe Billmann; Hellerud, Bernt Christian; Lindstad, Julie; Nielsen, Erik Waage; Bergseth, Grethe; Fadnes, Dag; Abrahamsen, Tore G.; Høiby, E. Arne; Schejbel, Lone; Garred, Peter; Lambris, John D.; Harboe, Morten (2009-09-15). "Human genetic deficiencies reveal the roles of complement in the inflammatory network: Lessons from nature". Proceedings of the National Academy of Sciences of the United States of America. 106 (37): 15861–15866. Bibcode:2009PNAS..10615861L. doi:10.1073/pnas.0903613106. ISSN 0027-8424. PMC 2732707. PMID 19717455. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732707" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732707</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Fischer, Alain (2022). "Chapter 351: Primary Immune Deficiency Diseases". Harrison's Principles of Internal Medicine (21st ed.). New York: McGraw Hill. ISBN 978-1-264-26850-4. <a href="978-1-264-26850-4" target="_blank">978-1-264-26850-4</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Reis, Edimara S.; Berger, Nadja; Wang, Xin; Koutsogiannaki, Sophia; Doot, Robert K.; Gumas, Justin T.; Foukas, Periklis G.; Resuello, Ranillo R.G.; Tuplano, Joel V.; Kukis, David; Tarantal, Alice F.; Young, Anthony J.; Kajikawa, Tetsuhiro; Soulika, Athena M.; Mastellos, Dimitrios C. (December 2018). "Safety profile after prolonged C3 inhibition". Clinical Immunology. 197: 96–106. doi:10.1016/j.clim.2018.09.004. ISSN 1521-6616. PMC 6258316. PMID 30217791. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258316" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258316</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Fischer, Alain (2022). "Chapter 351: Primary Immune Deficiency Diseases". Harrison's Principles of Internal Medicine (21st ed.). New York: McGraw Hill. ISBN 978-1-264-26850-4. <a href="978-1-264-26850-4" target="_blank">978-1-264-26850-4</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Fischer, Alain (2022). "Chapter 351: Primary Immune Deficiency Diseases". Harrison's Principles of Internal Medicine (21st ed.). New York: McGraw Hill. ISBN 978-1-264-26850-4. <a href="978-1-264-26850-4" target="_blank">978-1-264-26850-4</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> </ol>