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{{Infobox_gene}}
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'''Complement component 3''', often simply called '''C3''', is a [[protein]] of the [[immune system]]. It plays a central role in the [[complement system]] and contributes to [[innate immunity]]. In humans it is encoded on [[chromosome 19]] by a [[gene]] called ''C3''.<ref name="pmid2579379">{{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 = 708–12 | date = Feb 1985 | pmid = 2579379 | pmc = 397115 | doi = 10.1073/pnas.82.3.708 | url = http://www.pnas.org/content/82/3/708.abstract }}</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| accessdate = }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
C3 plays a central role in the activation of [[complement system]].<ref name="pmid11414361">{{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 | issue =  | pages = 35–48 | date = Apr 2001 | pmid = 11414361 | doi = 10.1034/j.1600-065X.2001.1800103.x }}</ref> 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="pmid768477">{{cite journal | vauthors = Lachmann P | title = Genetics of the complement system | journal = Journal of Medical Genetics | volume = 12 | issue = 4 | pages = 372–7 | date = Dec 1975 | pmid = 768477 | pmc = 1013316 | doi = 10.1136/jmg.12.4.372 }}</ref><ref name="pmid11813855">{{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 | volume = 40 | issue = 12 | pages = 1254–8 | date = Dec 2001 | pmid = 11813855 | doi = 10.2169/internalmedicine.40.1254 }}</ref>
| image = PBB_Protein_C3_image.jpg
| image_source = [[Protein Data Bank|PDB]] rendering based on 1c3d.
| PDB = {{PDB2|1c3d}}, {{PDB2|1ghq}}, {{PDB2|1w2s}}, {{PDB2|2a73}}, {{PDB2|2a74}}, {{PDB2|2b39}}, {{PDB2|2gox}}, {{PDB2|2hr0}}, {{PDB2|2i07}}, {{PDB2|2ice}}, {{PDB2|2icf}}
| Name = Complement component 3
| HGNCid = 1318
| Symbol = C3
| AltSymbols =; ASP; CPAMD1
| OMIM = 120700
| ECnumber =
  | Homologene = 68031
| MGIid = 88227
| Function = {{GNF_GO|id=GO:0004866 |text = endopeptidase inhibitor activity}} {{GNF_GO|id=GO:0005102 |text = receptor binding}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}}
| Process = {{GNF_GO|id=GO:0006954 |text = inflammatory response}} {{GNF_GO|id=GO:0006957 |text = complement activation, alternative pathway}} {{GNF_GO|id=GO:0006958 |text = complement activation, classical pathway}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 718
    | Hs_Ensembl =
    | Hs_RefseqProtein = NP_000055
    | Hs_RefseqmRNA = NM_000064
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr =
    | Hs_GenLoc_start =
    | Hs_GenLoc_end =
    | Hs_Uniprot =
    | Mm_EntrezGene = 12266
    | Mm_Ensembl = ENSMUSG00000024164
    | Mm_RefseqmRNA = NM_009778
    | Mm_RefseqProtein = NP_033908
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 17
    | Mm_GenLoc_start = 56889309
    | Mm_GenLoc_end = 56913426
    | Mm_Uniprot = Q207D2
  }}
}}
{{SI}}
{{CMG}}


==Overview==
One form of [[C3-convertase]], also known as C4b2a, is formed by a heterodimer of activated forms of C4 and C2. 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.
In immunology, soluble [[C3-convertase]], also known as C4b2a, catalyzes the [[proteolytic]] cleavage of C3 into [[C3a]] and [[C3b]] as part of the [[Complement system|classical complement system]] as well as the [[Mannan-binding lectin pathway]]. In the [[Alternative complement pathway]], C3 is instead cleaved by iC3Bb, another form of C3-convertase.


==See also==
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 that performs these cuts but it requires the help of another protein ([[Factor H]], CR1, MCP or C4BP) to supply [[cofactor (biochemistry)|cofactor]] activity.
*Complement system


==References==
== Structure ==
{{reflist|2}}
Several crystallographic structures of C3 have been determined<ref name="urlwww.ebi.ac.uk">{{cite web | url = http://www.ebi.ac.uk/pdbe-srv/view/search/index/?Uniprot_accession=P01024 | title =  Advanced search results for UniProt accession P01024 | author = | authorlink = | coauthors = | date = | format = | work = Protein Data Bank in Europe (PDBe)  | publisher =  European Bioinformatics Institute | pages = | archiveurl = | archivedate = | quote = | accessdate = 2010-12-27 }}</ref> and reveal that this protein contains 13 domains.<ref name="pmid16177781">{{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 = 505–11 | date = Sep 2005 | pmid = 16177781 | doi = 10.1038/nature04005 }}</ref><ref name="pmid17051160">{{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 = 213–6 | date = Nov 2006 | pmid = 17051160 | doi = 10.1038/nature05172 }}</ref><ref name="pmid17051150">{{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 = 217–20 | date = Nov 2006 | pmid = 17051150 | doi = 10.1038/nature05263 }}</ref><ref name="pmid16831446">{{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 = 115–27 | date = Aug 2006 | pmid = 16831446 | doi = 10.1016/j.jmb.2006.06.009 }}</ref>


==External links==
== Biochemistry ==
* {{cite journal |author=Sahu A, Lambris J |title=Structure and biology of complement protein C3, a connecting link between innate and acquired immunity |journal=Immunol Rev |volume=180 |issue= |pages=35–48 |year=2001 |pmid=11414361 |doi=10.1034/j.1600-065X.2001.1800103.x}}
 
* {{cite journal |author=Fredslund F, Jenner L, Husted L, Nyborg J, Andersen G, Sottrup-Jensen L |title=The structure of bovine complement component 3 reveals the basis for thioester function |journal=J Mol Biol |volume=361 |issue=1 |pages=115–27 |year=2006 |pmid=16831446 |doi=10.1016/j.jmb.2006.06.009}}
=== Biosynthesis ===
* {{PDB|2B39}}, {{PDB|2A73}}
In humans, C3 is predominantly synthesised by liver [[Hepatocyte|hepatocytes]]<ref name="pmid2579379" /> and to some degree by epidermis [[Keratinocyte|keratinocytes]].<ref name="MarcelCPasch">{{cite journal|last1=Pasch|first1=Marcel C.|last2=van den Bosch|first2=Norbert H.A.|last3=Bos|first3=Jan D.|last4=Asghar|first4=Syed S.|last5=Daha|first5=Mohamed R.|title=Synthesis of Complement Components C3 and Factor B in Human Keratinocytes is Differentially Regulated by Cytokines|journal=Journal of Investigative Dermatology|date=January 2000|volume=114|issue=1|page=78-82|doi=10.1046/j.1523-1747.2000.00841.x|url=http://www.jidonline.org/article/S0022-202X(15)40734-1/fulltext|accessdate=28 August 2017}}</ref>
*[http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?form=6&db=t&Dopt=s&uid=9222 domain structure]; protein database
 
== Clinical use ==
{{Complement test comparisons|align=left}}
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>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]].
{{-}}.
 
== Interactions ==
 
Complement component 3 has been shown to [[Protein-protein interaction|interact]] with [[Factor H]].<ref name="pmid9291131">{{cite journal | vauthors = Soames CJ, Sim RB | title = Interactions between human complement components factor H, factor I and C3b | journal = The Biochemical Journal | volume = 326 | issue = 2| pages = 553–61 | date = Sep 1997 | pmid = 9291131 | pmc = 1218704 | doi = 10.1042/bj3260553}}</ref><ref name="pmid11367533">{{cite journal | vauthors = Jokiranta TS, Westin J, Nilsson UR, Nilsson B, Hellwage J, Löfås S, Gordon DL, Ekdahl KN, Meri S | title = Complement C3b interactions studied with surface plasmon resonance technique | journal = International Immunopharmacology | volume = 1 | issue = 3 | pages = 495–506 | date = Mar 2001 | pmid = 11367533 | doi = 10.1016/S1567-5769(00)00042-4 }}</ref>
{{-}}
 
==Pathology==
Deficiencies in C3 lead to generic infections, usually fatal to the newborn.<ref>{{cite book | last1 = Abbas | first1 = Abul K. | last2 = Lichtman | first2 = Andrew H. | last3 = Pillai | first3 = Shiv | title = Basic Immunology: Functions and Disorders of the Immune System | date = 2012 | publisher = Elsevier Saunders | location = Philadelphia, PA | isbn = 978-1-4557-0707-2 | edition = Fourth | page = 162 | chapter = Chapter 8: Effector Mechanisms of Humoral Immunity | chapter-url = https://www.amazon.co.uk/Basic-Immunology-Functions-Disorders-Immune/dp/1455707074/ }}</ref>
 
== References ==
{{reflist|30em}}
 
== Further reading ==
{{refbegin | 1}}
* {{cite journal | vauthors = Bradley DT, Zipfel PF, Hughes AE | title = Complement in age-related macular degeneration: a focus on function | journal = Eye | volume = 25 | issue = 6 | pages = 683–93 | 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}}
* {{MeshName|Complement+C3}}


{{Complement_system}}
{{Complement_system}}
{{Acute phase proteins}}
{{Acute phase proteins}}
{{NLM content}}


[[Category:Complement system]]
[[Category:Complement system]]
{{WH}}
{{WS}}

Revision as of 16:02, 30 August 2017

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Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.[1][2]

Function

C3 plays a central role in the activation of complement system.[3] Its activation is required for both classical and alternative complement activation pathways. People with C3 deficiency are susceptible to bacterial infection.[4][5]

One form of C3-convertase, also known as C4b2a, is formed by a heterodimer of activated forms of C4 and C2. It catalyzes the proteolytic cleavage of C3 into 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 ASP, and C3b serves as an opsonizing agent. 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 that performs these cuts but it requires the help of another protein (Factor H, CR1, MCP or C4BP) to supply cofactor activity.

Structure

Several crystallographic structures of C3 have been determined[6] and reveal that this protein contains 13 domains.[7][8][9][10]

Biochemistry

Biosynthesis

In humans, C3 is predominantly synthesised by liver hepatocytes[1] and to some degree by epidermis keratinocytes.[11]

Clinical use

Complement tests
C4 (C) FB (A) C3 CH50 Conditions
 · ↓ ↓ ↓ PSG, C3 NeF AA
↓  · ↓  · HAE, C4D
 ·  ·  · ↓ TCPD
↓  · /↓ ↓ ↓ SLE
↑ ↑ ↑ ↑ inflammation

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)[12] and some types of kidney disease such as post-infectious glomerulonephritis, membranoproliferative glomerulonephritis, and shunt nephritis.

.

Interactions

Complement component 3 has been shown to interact with Factor H.[13][14]

Pathology

Deficiencies in C3 lead to generic infections, usually fatal to the newborn.[15]

References

  1. ↑ 1.0 1.1 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. doi:10.1073/pnas.82.3.708. PMC 397115. PMID 2579379.
  2. ↑ "Entrez Gene: C3 complement component 3".
  3. ↑ Sahu A, Lambris JD (Apr 2001). "Structure and biology of complement protein C3, a connecting link between innate and acquired immunity". Immunological Reviews. 180: 35–48. doi:10.1034/j.1600-065X.2001.1800103.x. PMID 11414361.
  4. ↑ Lachmann P (Dec 1975). "Genetics of the complement system". Journal of Medical Genetics. 12 (4): 372–7. doi:10.1136/jmg.12.4.372. PMC 1013316. PMID 768477.
  5. ↑ Matsuyama W, Nakagawa M, Takashima H, Muranaga F, Sano Y, Osame M (Dec 2001). "Molecular analysis of hereditary deficiency of the third component of complement (C3) in two sisters". Internal Medicine. 40 (12): 1254–8. doi:10.2169/internalmedicine.40.1254. PMID 11813855.
  6. ↑ "Advanced search results for UniProt accession P01024". Protein Data Bank in Europe (PDBe). European Bioinformatics Institute. Retrieved 2010-12-27.
  7. ↑ Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K, Nilsson B, Gros P (Sep 2005). "Structures of complement component C3 provide insights into the function and evolution of immunity". Nature. 437 (7058): 505–11. doi:10.1038/nature04005. PMID 16177781.
  8. ↑ Janssen BJ, Christodoulidou A, McCarthy A, Lambris JD, Gros P (Nov 2006). "Structure of C3b reveals conformational changes that underlie complement activity". Nature. 444 (7116): 213–6. doi:10.1038/nature05172. PMID 17051160.
  9. ↑ Wiesmann C, Katschke KJ, Yin J, Helmy KY, Steffek M, Fairbrother WJ, McCallum SA, Embuscado L, DeForge L, Hass PE, van Lookeren Campagne M (Nov 2006). "Structure of C3b in complex with CRIg gives insights into regulation of complement activation". Nature. 444 (7116): 217–20. doi:10.1038/nature05263. PMID 17051150.
  10. ↑ Fredslund F, Jenner L, Husted LB, Nyborg J, Andersen GR, Sottrup-Jensen L (Aug 2006). "The structure of bovine complement component 3 reveals the basis for thioester function". Journal of Molecular Biology. 361 (1): 115–27. doi:10.1016/j.jmb.2006.06.009. PMID 16831446.
  11. ↑ Pasch, Marcel C.; van den Bosch, Norbert H.A.; Bos, Jan D.; Asghar, Syed S.; Daha, Mohamed R. (January 2000). "Synthesis of Complement Components C3 and Factor B in Human Keratinocytes is Differentially Regulated by Cytokines". Journal of Investigative Dermatology. 114 (1): 78-82. doi:10.1046/j.1523-1747.2000.00841.x. Retrieved 28 August 2017.
  12. ↑ https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=complement_c3_blood
  13. ↑ Soames CJ, Sim RB (Sep 1997). "Interactions between human complement components factor H, factor I and C3b". The Biochemical Journal. 326 (2): 553–61. doi:10.1042/bj3260553. PMC 1218704. PMID 9291131.
  14. ↑ Jokiranta TS, Westin J, Nilsson UR, Nilsson B, Hellwage J, Löfås S, Gordon DL, Ekdahl KN, Meri S (Mar 2001). "Complement C3b interactions studied with surface plasmon resonance technique". International Immunopharmacology. 1 (3): 495–506. doi:10.1016/S1567-5769(00)00042-4. PMID 11367533.
  15. ↑ Abbas, Abul K.; Lichtman, Andrew H.; Pillai, Shiv (2012). "Chapter 8: Effector Mechanisms of Humoral Immunity". Basic Immunology: Functions and Disorders of the Immune System (Fourth ed.). Philadelphia, PA: Elsevier Saunders. p. 162. ISBN 978-1-4557-0707-2.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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