View source for C3a (complement)

[[Image:Complement pathway.svg|thumb|right|270px|The classical and alternative complement pathways.]]
'''C3a''' is one of the proteins formed by the cleavage of [[complement component 3]]; the other is [[C3b]]. C3a is a 77 residue [[anaphylatoxin]] that binds to the C3a receptor (C3aR), a class A [[G protein-coupled receptor]]. It plays a large role in the immune response.

C3a molecules induce responses through the GPCR C3a receptor. Like other anaphylatoxins, C3a is regulated by cleavage of its carboxy-terminal arginine, which results in a molecule with lowered inflammatory function (C3a desarginine).<ref name=":0" />

C3a is an effector of the complement system with a range of functions including [[T cell]] activation and survival,<ref name=":2">{{cite journal|last1 = Strainic|first1 = MG|last2 = Liu|first2 = J|last3 = Huang|first3 = D|last4 = An|first4 = F|last5 = Lalli|first5 = PN|last6 = Muqim|first6 = N|last7 = Shapiro|first7 = VS|last8 = Dubyak|first8 = GR|last9 = Heeger|first9 = PS|last10 = Medof|first10 = ME|title = Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells.|journal = Immunity|date = March 2008|volume = 28|issue = 3|pages = 425–35|pmid = 18328742|doi=10.1016/j.immuni.2008.02.001|pmc=2646383}}</ref> [[angiogenesis]] stimulation,<ref>{{cite journal|last1 = Khan|first1 = MA|last2 = Assiri|first2 = AM|last3 = Broering|first3 = DC|title = Complement and macrophage crosstalk during process of angiogenesis in tumor progression|journal = Journal of Biomedical Science|date = 22 July 2015|volume = 22| issue=1 |pages = 58|pmid = 26198107|doi=10.1186/s12929-015-0151-1|pmc=4511526 | doi-access=free }}</ref> [[chemotaxis]], [[mast cell]] degranulation,<ref>{{cite journal |last1=Reid |first1=Robert C. |last2=Yau |first2=Mei-Kwan |last3=Singh |first3=Ranee |last4=Hamidon |first4=Johan K. |last5=Reed |first5=Anthony N. |last6=Chu |first6=Peifei |last7=Suen |first7=Jacky Y. |last8=Stoermer |first8=Martin J. |last9=Blakeney |first9=Jade S. |last10=Lim |first10=Junxian |last11=Faber |first11=Jonathan M. |last12=Fairlie |first12=David P. |title=Downsizing a human inflammatory protein to a small molecule with equal potency and functionality |journal=Nature Communications |date=21 November 2013 |volume=4 |issue=1 |pages=2802 |doi=10.1038/ncomms3802 |pmid=24257095 |bibcode=2013NatCo...4.2802R |s2cid=5465825 |language=en |issn=2041-1723|doi-access=free }}</ref> and [[macrophage]] activation.<ref>{{cite journal|last1 = Mathern|first1 = DR|last2 = Heeger|first2 = PS|title = Molecules Great and Small: The Complement System.|journal = Clinical Journal of the American Society of Nephrology|date = 4 September 2015|volume = 10|issue = 9|pages = 1636–50|pmid = 25568220|doi=10.2215/cjn.06230614|pmc = 4559511}}</ref> It has been shown to have both proinflammatory and anti-inflammatory responses, its activity able to counteract the proinflammatory effects of [[Complement component 5a|C5a]].<ref name="Coulthard">{{cite journal|last1 = Coulthard|first1 = LG|last2 = Woodruff|first2 = TM|title = Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth.|journal = Journal of Immunology|date = 15 April 2015|volume = 194|issue = 8|pages = 3542–8|pmid = 25848071|doi=10.4049/jimmunol.1403068|doi-access = free}}</ref>

Initial research in mice demonstrating an effective treatment after stroke is leading to further investigation to determine whether application to humans has potential.<ref>Anna Stokowska, Markus Aswendt, Daniel Zucha, Stephanie Lohmann, Frederique Wieters, Javier Morán Suarez, Alison L. Atkins, YiXian Li, Maria Miteva, Julia Lewin, Dirk Wiedermann, Michael Diedenhofen, Åsa Torinsson Naluai, Pavel Abaffy, Lukas Valihrach, Mikael Kubista, Mathias Hoehn, Milos Pekny, and Marcela Pekna, ''[https://www.jci.org/articles/view/162253 Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity]'', Journal of Clinical Investigation, March 30, 2023</ref>

== Structure ==

=== C3a ===
C3a is a strongly basic and highly cationic 77 residue protein with a molecular mass of approximately 10 kDa.<ref>{{Cite journal|title = The new face of anaphylatoxins in immune regulation|journal = Immunobiology|date = 2012-02-01|issn = 1878-3279|pmid = 21856033|pages = 225–234|volume = 217|issue = 2|doi = 10.1016/j.imbio.2011.07.016|first = Wuding|last = Zhou}}</ref> Residues 17-66 are made up of three anti-parallel helices and three disulfide bonds, which confer stability to the protein. The N-terminus consists of a fourth flexible helical structure, while the C terminus is disordered.<ref>{{Cite journal|title = Denaturation and unfolding of human anaphylatoxin C3a: An unusually low covalent stability of its native disulfide bonds|journal = Archives of Biochemistry and Biophysics|date = 2008-12-15|pmc = 2636726|pmid = 18854167|pages = 104–110|volume = 480|issue = 2|doi = 10.1016/j.abb.2008.09.013|first1 = Jui-Yoa|last1 = Chang|first2 = Curtis C. -J.|last2 = Lin|first3 = Silvia|last3 = Salamanca|first4 = Michael K.|last4 = Pangburn|first5 = Rick A.|last5 = Wetsel}}</ref> C3a has a regulatory process and a structure homologous to complement component [[Complement component 5a|C5a]], with which it shares 36% of its sequence identity.<ref name=":0">{{Cite journal|title = Human C3a and C3a desArg anaphylatoxins have conserved structures, in contrast to C5a and C5a desArg|journal = Protein Science|date = 2013-02-01|issn = 1469-896X|pmc = 3588916|pmid = 23184394|pages = 204–212|volume = 22|issue = 2|doi = 10.1002/pro.2200|first1 = Goran|last1 = Bajic|first2 = Laure|last2 = Yatime|first3 = Andreas|last3 = Klos|first4 = Gregers Rom|last4 = Andersen}}</ref>

=== Receptor ===
C3a induces an immunological response through a 482 residue G-protein-coupled receptor called [[C3a receptor]] (C3aR). The C3aR is similarly structurally homologous to C5aR, but contains an extracellular domain with more than 160 amino acids.<ref>{{Cite journal|title = Molecular cloning and characterization of the human anaphylatoxin C3a receptor|journal = The Journal of Biological Chemistry|date = 1996-08-23|issn = 0021-9258|pmid = 8702752|pages = 20231–20234|volume = 271|issue = 34|first1 = R. S.|last1 = Ames|first2 = Y.|last2 = Li|first3 = H. M.|last3 = Sarau|first4 = P.|last4 = Nuthulaganti|first5 = J. J.|last5 = Foley|first6 = C.|last6 = Ellis|first7 = Z.|last7 = Zeng|first8 = K.|last8 = Su|first9 = A. J.|last9 = Jurewicz|doi=10.1074/jbc.271.34.20231|doi-access = free}}</ref> Specific binding sites for interactions between C3a and C3aR are unknown, but it has been shown that sulfation of tyrosine 174, one of the amino acids in the extracellular domain, is required for C3a binding.<ref>{{Cite journal|title = Sulfation of tyrosine 174 in the human C3a receptor is essential for binding of C3a anaphylatoxin|journal = The Journal of Biological Chemistry|date = 2003-09-26|issn = 0021-9258|pmid = 12871936|pages = 37902–37908|volume = 278|issue = 39|doi = 10.1074/jbc.M306061200|first1 = Jinming|last1 = Gao|first2 = Hyeryun|last2 = Choe|first3 = Dalena|last3 = Bota|first4 = Paulette L.|last4 = Wright|first5 = Craig|last5 = Gerard|first6 = Norma P.|last6 = Gerard|doi-access = free}}</ref> It has also been demonstrated that the C3aR N terminus is not required for ligand binding.<ref>{{Cite journal|title = Chimeric receptors of the human C3a receptor and C5a receptor (CD88)|journal = The Journal of Biological Chemistry|date = 1999-03-26|issn = 0021-9258|pmid = 10085065|pages = 8367–8370|volume = 274|issue = 13|first1 = T.|last1 = Crass|first2 = R. S.|last2 = Ames|first3 = H. M.|last3 = Sarau|first4 = M. A.|last4 = Tornetta|first5 = J. J.|last5 = Foley|first6 = J.|last6 = Köhl|first7 = A.|last7 = Klos|first8 = W.|last8 = Bautsch|doi=10.1074/jbc.274.13.8367|doi-access = free}}</ref>

== Formation ==
C3a formation occurs through activation and cleavage of [[complement component 3]] in a reaction catalyzed by [[C3-convertase]]. There are three pathways of activation, each of which leads to the formation of C3a and [[C3b]], which is involved in antigen opsonization. Other than the alternative pathway, which is constantly active, C3a formation is triggered by pathogenic infection.

=== Classical pathway ===
The classical pathway of complement activation is initiated when the [[C1 complex]], made up of C1r and C1s serine proteases, recognizes the Fc region of IgM or IgG antibodies bound to a pathogen. [[C1q]] mediates the classical pathway by activating the C1 complex, which cleaves C4 and C2 into smaller fragments (C4a, C4b, C2a, and C2b). C4a and C2b form C4bC2b, also known as C3 convertase.<ref>{{Cite journal|title = Structural biology of C1: dissection of a complex molecular machinery|journal = Immunological Reviews|date = 2001-04-01|issn = 0105-2896|pmid = 11414355|pages = 136–145|volume = 180|first1 = G. J.|last1 = Arlaud|first2 = C.|last2 = Gaboriaud|first3 = N. M.|last3 = Thielens|first4 = V.|last4 = Rossi|first5 = B.|last5 = Bersch|first6 = J. F.|last6 = Hernandez|first7 = J. C.|last7 = Fontecilla-Camps|doi=10.1034/j.1600-065x.2001.1800112.x| s2cid=21136630 }}</ref>

=== Lectin pathway ===
The lectin pathway is activated when pattern-recognition receptors, like mannan-binding lectin or ficolins, recognize and bind to [[pathogen-associated molecular pattern]]s on the antigen, including sugars.<ref name=":1">{{Cite journal|last1=Dunkelberger|first1=Jason R.|last2=Song|first2=Wen-Chao|date=2010-01-01|title=Complement and its role in innate and adaptive immune responses|journal=Cell Research|volume=20|issue=1|pages=34–50|doi=10.1038/cr.2009.139|issn=1748-7838|pmid=20010915|doi-access=free}}</ref> These bound receptors then complex with Mannose-Binding Lectin-Associated Serine Proteases (MASPs), which have proteolytic activity similar to the C1 complex. The MASPs cleave C4 and C2, resulting in C3 convertase formation.<ref>{{Cite journal|title = New perspectives on mannan-binding lectin-mediated complement activation|journal = Immunobiology|date = 2007-01-01|issn = 0171-2985|pmid = 17544815|pages = 301–311|volume = 212|issue = 4–5|doi = 10.1016/j.imbio.2006.12.004|first1 = Søren E.|last1 = Degn|first2 = Steffen|last2 = Thiel|first3 = Jens C.|last3 = Jensenius|doi-access = free}}</ref>

=== Alternative pathway ===
The [[Alternative complement pathway|alternative pathway of complement activation]] is typically always active at low levels in blood plasma through a process called tick-over, in which C3 spontaneously hydrolyzes into its active form, C3(H<sub>2</sub>O). This activation induces a conformational change in the thioester domain of C3(H<sub>2</sub>O) that allows it to bind to a plasma protein called Factor B. This complex is then cleaved by [[Factor D]], a serine protease, to form C3b(H<sub>2</sub>O)Bb, or fluid-phase C3-convertase. This complex has the ability to catalyze the formation of C3a and C3b after it binds [[properdin]], a globulin protein, and is stabilized.<ref>{{Cite journal|title = Complement System Part I - Molecular Mechanisms of Activation and Regulation|journal = Frontiers in Immunology|date = 2015-01-01|issn = 1664-3224|pmc = 4451739|pmid = 26082779|pages = 262|volume = 6|doi = 10.3389/fimmu.2015.00262|first1 = Nicolas S.|last1 = Merle|first2 = Sarah Elizabeth|last2 = Church|first3 = Veronique|last3 = Fremeaux-Bacchi|first4 = Lubka T.|last4 = Roumenina| doi-access=free }}</ref>

== Functions ==
Anaphylatoxins are small complement peptides that induce proinflammatory responses in tissues. C3a is primarily regarded for its role in the [[innate immunity|innate]] and [[adaptive immune response]]s as an anaphylatoxin, moderating and activating multiple inflammatory pathways.

=== Role in innate immunity ===
The roles of C3a in innate immunity, upon binding C3aR, include increased vasodilation via endothelial cell contraction, increased vascular permeability, and mast cell and basophil degranulation of histamine, induction of respiratory burst and subsequent degradation of pathogens by neutrophils, macrophages, and eosinophils, and regulation of cationic eosinophil protein migration, adhesion, and production.<ref>{{Cite journal|last1=Klos|first1=Andreas|last2=Tenner|first2=Andrea J.|last3=Johswich|first3=Kay-Ole|last4=Ager|first4=Rahasson R.|last5=Reis|first5=Edimara S.|last6=Köhl|first6=Jörg|date=2009-09-01|title=The role of the anaphylatoxins in health and disease|journal=Molecular Immunology|series=12th European Meeting on Complement in Human Disease12th European Meeting on CHD12th European Meeting on Complement in Human Disease|volume=46|issue=14|pages=2753–2766|doi=10.1016/j.molimm.2009.04.027|pmc=2725201|pmid=19477527}}</ref> C3a is also able to play a role in chemotaxis for mast cells and eosinophils, but C5a is a more potent chemoattractant.<ref>{{Cite journal|last1=Schraufstatter|first1=Ingrid U.|last2=DiScipio|first2=Richard G.|last3=Zhao|first3=Ming|last4=Khaldoyanidi|first4=Sophia K.|date=2009-03-15|title=C3a and C5a Are Chemotactic Factors for Human Mesenchymal Stem Cells, Which Cause Prolonged ERK1/2 Phosphorylation|journal=The Journal of Immunology|language=en|volume=182|issue=6|pages=3827–3836|doi=10.4049/jimmunol.0803055|issn=0022-1767|pmid=19265162|doi-access=free}}</ref>

Traditionally thought to serve a strictly pro-inflammatory role, recent investigations have shown that C3a can also work against C5a to serve an anti-inflammatory role. In addition, migration and degranulation of neutrophils can be suppressed in the presence of C3a.<ref name ="Coulthard"/>

=== Role in adaptive immunity ===
C3a also plays an important role in adaptive immunity, moderating leukocyte production and proliferation. C3a is able to regulate B cell and monocyte production of IL-6 and TNF-α, and human C3a has been shown to dampen the polyclonal immune response through dose-dependent regulation of B cell molecule production.<ref name=":3">{{Cite journal|last1=Merle|first1=Nicolas S.|last2=Noe|first2=Remi|last3=Halbwachs-Mecarelli|first3=Lise|last4=Fremeaux-Bacchi|first4=Veronique|last5=Roumenina|first5=Lubka T.|date=2015-05-26|title=Complement System Part II: Role in Immunity|journal=Frontiers in Immunology|volume=6|pages=257|doi=10.3389/fimmu.2015.00257|issn=1664-3224|pmc=4443744|pmid=26074922|doi-access=free }}</ref> C3aR signaling along antigen-presenting cells' CD28 and CD40L pathways also plays a role in T cell proliferation and differentiation.<ref name=":2" /> C3aR has been shown to be necessary for TH1 cell generation and regulates TH1 IL-10 expression, while an absence of active C3aR on dendritic cells upregulates [[regulatory T cell]] production. The absence of C3 has also been shown to decrease IL-2 receptor expression on T cells.<ref name=":3" />

== Regulation ==

=== Regulation of complement activation ===
Levels of complement are regulated by moderating convertase formation and enzymatic activity. C3 convertase formation is primarily regulated by levels of active C3b and C4b. Factor I, a serine protease activated by cofactors, can cleave and C3b and C4b, thus preventing convertase formation. C3 convertase activity is also regulated without C3b inactivation, through [[complement control protein]]s, including [[decay-accelerating factor]]s that function to speed up C3 convertase half-lives and avert convertase formation.<ref name=":1" />

=== Deactivation ===
C3a, like other anaphylatoxins, has a C-terminal arginine residue. Serum [[carboxypeptidase B]], a protease, cleaves the arginine residue from C3a, forming the desArg derivative of C3a, also known as [[Acylation stimulating protein|acylation stimulating protein (ASP)]]. Unlike C5a desArg, this version of C3a has no proinflammatory activity.<ref name=":0"/> However, ASP functions as a hormone in the adipose tissue, moderating fatty acid migration to adipocytes and triacylglycerol synthesis.<ref>{{Cite journal|last1=Barbu|first1=Andreea|last2=Hamad|first2=Osama A.|last3=Lind|first3=Lars|last4=Ekdahl|first4=Kristina N.|last5=Nilsson|first5=Bo|date=2015-09-01|title=The role of complement factor C3 in lipid metabolism|journal=Molecular Immunology|series=15th European Meeting on Complement in Human Disease 2015, Uppsala, Sweden|volume=67|issue=1|pages=101–107|doi=10.1016/j.molimm.2015.02.027|pmid=25746915}}</ref> In addition, it has been shown that ASP downregulates the polyclonal immune response in the same way C3a does.<ref name=":1" />

==References==
{{reflist}}

*{{Cite journal | doi =10.6072/H0.MP.A004235.01 | title =Complement C3 (Human) | year =2012 | last1 =Dinasarapu | first1 =A R | last2 =Chandrasekhar | first2 =A | last3 =Sahu | first3 =A | last4 =Subramaniam | first4 =S | journal =UCSD Molecule Pages | issue =2 | url=https://escholarship.org/uc/item/07h8p9hg}}

==External links==
* http://www.merck.com/mmpe/sec13/ch163/ch163d.html

{{Complement system}}

[[Category:Complement system]]