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2025-06-20T15:36:41Z

Clinical signficance: typo

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{{Short description|Protein found in humans}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox gene}}
'''Complement component 3''', often simply called '''C3''', is a [[protein]] of the [[immune system]] that is found primarily in the blood. It plays a central role in the [[complement system]] of vertebrate animals and contributes to [[innate immunity]]. In humans it is encoded on [[chromosome 19]] by a [[gene]] called ''C3''.<ref name="de_Bruijn_1985">{{cite journal | vauthors = de Bruijn MH, Fey GH | title = Human complement component C3: cDNA coding sequence and derived primary structure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 3 | pages = 708–712 | date = Feb 1985 | pmid = 2579379 | pmc = 397115 | doi = 10.1073/pnas.82.3.708 | bibcode = 1985PNAS...82..708D | doi-access = free }}</ref><ref name="entrez_718">{{cite web | title = Entrez Gene: C3 complement component 3 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=718 }}</ref>

Deficiencies and defects of C3 result in the affected person being [[Immunodeficiency|immunocompromised]] and particularly vulnerable to [[Pathogenic bacteria|bacterial infections]].

== Structure ==

Complement component 3 (C3) is a large, multidomain glycoprotein that is composed of two polypeptide chains-an α-chain (approximately 110 kDa) and a β-chain (approximately 75 kDa)-which are covalently linked by a single disulfide bond and further associated through non-covalent interactions.<ref name="Sahu_2001">{{cite journal | vauthors = Sahu A, Lambris JD | title = Structure and biology of complement protein C3, a connecting link between innate and acquired immunity | journal = Immunological Reviews | volume = 180 | pages = 35–48 | date = April 2001 | pmid = 11414361 | doi = 10.1034/j.1600-065x.2001.1800103.x }}</ref><ref name="Vogel_2010">{{cite journal | vauthors = Vogel CW, Fritzinger DC | title = Cobra venom factor: Structure, function, and humanization for therapeutic complement depletion | journal = Toxicon| volume = 56 | issue = 7 | pages = 1198–1222 | date = December 2010 | pmid = 20417224 | doi = 10.1016/j.toxicon.2010.04.007 | bibcode = 2010Txcn...56.1198V }}</ref> The mature human C3 protein contains 1,641 amino acids and is organized into thirteen distinct domains, nine of which were unpredicted prior to crystallographic studies.<ref name="Janssen_2005" /><ref name="Geisbrecht_2022">{{cite journal | vauthors = Geisbrecht BV, Lambris JD, Gros P | title = Complement component C3: A structural perspective and potential therapeutic implications | journal = Seminars in Immunology | volume = 59 | pages = 101627 | date = January 2022 | pmid = 35760703 | pmc = 9842190 | doi = 10.1016/j.smim.2022.101627 }}</ref> These domains fold into a highly asymmetrical shape, with six domains derived from the α and β chains.<ref name="Geisbrecht_2022" /> C3 contains two main N-linked glycosylation sites: Asn-917 on the α-chain and Asn-63 on the β-chain, which together account for about 1.5% of its molecular weight.<ref name="Sahu_2001" /> A unique feature of C3 is its internal thioester bond, formed during post-translational modification, which is essential for covalent attachment of activated C3b to target surfaces.<ref name="Janssen_2005" /> Upon activation by C3 convertase, the α-chain is cleaved, releasing the anaphylatoxin C3a and generating C3b, which exposes the reactive thioester group. The structure of C3 is highly flexible, particularly in the α-chain, allowing for marked conformational changes that are critical for its activation, regulation, and diverse biological functions.<ref name="Janssen_2005" />

Several crystallographic structures of C3 have been determined<ref name="cite49dece6f">{{cite web | title = Advanced search results for UniProt accession P01024 | url = http://www.ebi.ac.uk/pdbe-srv/view/search/index/?Uniprot_accession=P01024 | work = Protein Data Bank in Europe (PDBe) | publisher = European Bioinformatics Institute | access-date = 2010-12-27 }}</ref> and reveal that this protein contains 13 domains.<ref name="Janssen_2005">{{cite journal | vauthors = Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K, Nilsson B, Gros P | title = Structures of complement component C3 provide insights into the function and evolution of immunity | journal = Nature | volume = 437 | issue = 7058 | pages = 505–511 | date = Sep 2005 | pmid = 16177781 | doi = 10.1038/nature04005 | bibcode = 2005Natur.437..505J | hdl = 1874/14832 | s2cid = 4344273 | hdl-access = free }}</ref><ref name="Janssen_2006">{{cite journal | vauthors = Janssen BJ, Christodoulidou A, McCarthy A, Lambris JD, Gros P | title = Structure of C3b reveals conformational changes that underlie complement activity | journal = Nature | volume = 444 | issue = 7116 | pages = 213–216 | date = Nov 2006 | pmid = 17051160 | doi = 10.1038/nature05172 | bibcode = 2006Natur.444..213J | hdl = 1874/20065 | s2cid = 4333755 | hdl-access = free }}</ref><ref name="Wiesmann_2006">{{cite journal | vauthors = Wiesmann C, Katschke KJ, Yin J, Helmy KY, Steffek M, Fairbrother WJ, McCallum SA, Embuscado L, DeForge L, Hass PE, van Lookeren Campagne M | title = Structure of C3b in complex with CRIg gives insights into regulation of complement activation | journal = Nature | volume = 444 | issue = 7116 | pages = 217–220 | date = Nov 2006 | pmid = 17051150 | doi = 10.1038/nature05263 | bibcode = 2006Natur.444..217W | s2cid = 4372953 }}</ref><ref name="Fredslund_2006">{{cite journal | vauthors = Fredslund F, Jenner L, Husted LB, Nyborg J, Andersen GR, Sottrup-Jensen L | title = The structure of bovine complement component 3 reveals the basis for thioester function | journal = Journal of Molecular Biology | volume = 361 | issue = 1 | pages = 115–127 | date = Aug 2006 | pmid = 16831446 | doi = 10.1016/j.jmb.2006.06.009 }}</ref>
<br>
The [https://www.uniprot.org/uniprot/P01024 C3 precursor protein] 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).

== Function ==
C3 plays a central role in the activation of the [[complement system]].<ref name="Sahu_2001" /> Its activation is required for both [[complement system|classical]] and [[alternative complement pathway|alternative complement activation]] pathways. People with C3 deficiency are susceptible to bacterial infection.<ref name="Lachmann_1975">{{cite journal | vauthors = Lachmann P | title = Genetics of the complement system | journal = Journal of Medical Genetics | volume = 12 | issue = 4 | pages = 372–377 | date = Dec 1975 | pmid = 768477 | pmc = 1013316 | doi = 10.1136/jmg.12.4.372 }}</ref><ref name="Matsuyama_2001">{{cite journal | vauthors = Matsuyama W, Nakagawa M, Takashima H, Muranaga F, Sano Y, Osame M | title = Molecular analysis of hereditary deficiency of the third component of complement (C3) in two sisters | journal = Internal Medicine | location = Tokyo, Japan | volume = 40 | issue = 12 | pages = 1254–1258 | date = Dec 2001 | pmid = 11813855 | doi = 10.2169/internalmedicine.40.1254 | doi-access = free }}</ref>

One form of [[C3-convertase]], also known as C4b2b (formally known as C4b2a), is formed by a heterodimer of activated forms of C4 and C2.<ref>{{Cite journal | vauthors = Garred P, Kemper C, Tenner AJ, Bohlson SS | title = Complement Nomenclature—Deconvoluted | journal = Frontiers in Immunology | volume = 10 | pages = 1308 | date = 2019-06-07 | pmid = 31231398 | pmc = 6568193 | doi = 10.3389/fimmu.2019.01308 | issn = 1664-3224 | doi-access = free }}</ref> It catalyzes the [[proteolytic]] cleavage of C3 into [[C3a (complement)|C3a]] and [[C3b]], generated during activation through the classical pathway as well as the [[lectin pathway]]. C3a is an [[anaphylotoxin]] and the precursor of some cytokines such as [[Acylation stimulating protein|ASP]], and C3b serves as an [[opsonin|opsonizing]] agent. [[Complement factor I|Factor I]] can cleave C3b into C3c and C3d, the latter of which plays a role in enhancing [[B cell]] responses. In the alternative complement pathway, C3 is cleaved by C3bBb, another form of C3-convertase composed of activated forms of C3 (C3b) and [[factor B]] (Bb). Once C3 is activated to C3b, it exposes a reactive [[thioester]] that allows the peptide to covalently attach to any surface that can provide a [[nucleophile]] 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.

C3bBb is deactivated in steps. First, the proteolytic component of the convertase, Bb, is removed by complement regulatory proteins having [[decay-accelerating factor]] (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 [[cofactor (biochemistry)|cofactor]] (e.g [[Factor H]], CR1, MCP or C4BP) for activity.

== Biosynthesis ==
In humans, C3 is predominantly synthesised by liver [[hepatocyte]]s<ref name="de_Bruijn_1985" /> and to some degree by epidermis [[keratinocyte]]s.<ref name="Pasch_2000">{{cite journal | vauthors = Pasch MC, van den Bosch NH, Bos JD, Asghar SS, Daha MR | title = Synthesis of Complement Components C3 and Factor B in Human Keratinocytes is Differentially Regulated by Cytokines | journal = The Journal of Investigative Dermatology | volume = 114 | issue = 1 | pages = 78–82 | date = January 2000 | pmid = 10620119 | doi = 10.1046/j.1523-1747.2000.00841.x | url = http://www.jidonline.org/article/S0022-202X(15)40734-1/fulltext | access-date = 28 August 2017 | doi-access = free }}</ref>

== Regulation ==

[[Factor H]] is the primary [[Regulator gene|regulator]] of C3. Deficiency of Factor H may lead to uncontrolled C3 activity through the [[Alternative complement pathway|alternative pathway]] of the complement system.<ref>{{Cite journal | vauthors = Ruseva MM, Takahashi M, Fujita T, Pickering MC | title = C3 dysregulation due to factor H deficiency is mannan-binding lectin-associated serine proteases (MASP)-1 and MASP-3 independent in vivo | journal = Clinical and Experimental Immunology | volume = 176 | issue = 1 | pages = 84–92 | date = April 2014 | pmid = 24279761 | pmc = 3958157 | doi = 10.1111/cei.12244 | issn = 0009-9104 }}</ref>
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== Clinical significance ==
{{Complement test comparisons|align=right}}

=== Monitoring ===
Levels of C3 in the [[blood]] may be measured to support or refute a particular medical diagnosis. For example, low C3 levels are associated with Systemic Lupus Erythematosus (SLE)<ref>{{Cite web | title = Complement C3 (Blood) - Health Encyclopedia - University of Rochester Medical Center | url = https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=complement_c3_blood }}</ref>
and some types of kidney disease such as [[post-infectious glomerulonephritis]], [[membranoproliferative glomerulonephritis]], and [[shunt nephritis]].
{{Clear}}

=== Pathology ===
Deficiency of C3 results in the affected person being [[Immunodeficiency|immunocompromised]]. 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, [[Complement component 2|C2]], [[Complement component 4|C4]], 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.<ref name="Fischer_2022">{{Cite book | vauthors = Fischer A | chapter = Chapter 351: Primary Immune Deficiency Diseases | title = Harrison's Principles of Internal Medicine | location = New York | year = 2022 | publisher = McGraw Hill | isbn = 978-1-264-26850-4 | edition = 21st | language = English }}</ref>

Affected people are particularly vulnerable to infections with Gram-negative organisms such as pathogenic ''[[Escherichia coli|E. coli]]'' or ''[[Salmonella enterica]]''.<ref>{{Cite journal | vauthors = Lappegård KT, Christiansen D, Pharo A, Thorgersen EB, Hellerud BC, Lindstad J, Nielsen EW, Bergseth G, Fadnes D, Abrahamsen TG, Høiby EA, Schejbel L, Garred P, Lambris JD, Harboe M | title = Human genetic deficiencies reveal the roles of complement in the inflammatory network: Lessons from nature | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 37 | pages = 15861–15866 | date = 2009-09-15 | pmid = 19717455 | pmc = 2732707 | doi = 10.1073/pnas.0903613106 | doi-access = free | issn = 0027-8424 | bibcode = 2009PNAS..10615861L }}</ref> Additionally, C3 and other complement deficiencies are associated with frequent and severe [[Respiratory tract infection|respiratory infections]], as well as other infections that invade and penetrate tissue layers.<ref name="Fischer_2022" />

Some data shows that [[Acquired characteristic|acquired]] C3 deficiency, including when this is intentionally done for medical [[Immunosuppressive drug|immunosuppression]] purposes, may not significantly impact a person's immune function long-term.<ref>{{Cite journal | vauthors = Reis ES, Berger N, Wang X, Koutsogiannaki S, Doot RK, Gumas JT, Foukas PG, Resuello RR, Tuplano JV, Kukis D, Tarantal AF, Young AJ, Kajikawa T, Soulika AM, Mastellos DC | title = Safety profile after prolonged C3 inhibition | journal = Clinical Immunology | location = Orlando, Fla. | volume = 197 | pages = 96–106 | date = December 2018 | pmid = 30217791 | pmc = 6258316 | doi = 10.1016/j.clim.2018.09.004 | issn = 1521-6616 }}</ref> However, by contrast, [[Birth defect|congenital]] C3 deficiency is known to cause chronic illness.<ref name="Fischer_2022" />

Additionally, several forms of C3 deficiency contribute to the development of [[Lupus|systemic lupus erythematosus]] and other [[autoimmune disease]]s.<ref name="Fischer_2022" />

== References ==
{{reflist|30em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Bradley DT, Zipfel PF, Hughes AE | title = Complement in age-related macular degeneration: a focus on function | journal = Eye | location = London, England | volume = 25 | issue = 6 | pages = 683–693 | date = Jun 2011 | pmid = 21394116 | pmc = 3178140 | doi = 10.1038/eye.2011.37 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1367/ GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome]
* [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]
* [https://www.ncbi.nlm.nih.gov/books/NBK1425/ GeneReviews/NCBI/NIH/UW entry on Dense Deposit Disease/Membranoproliferative Glomerulonephritis Type II]
* {{MeshName|Complement+C3}}
* {{PDBe-KB2|P01024|Complement C3}}

{{Complement_system}}
{{Acute phase proteins}}

{{NLM content}}

[[Category:Complement system]]

Complement component 3 - Revision history

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