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Structure[edit]
C3a[edit]
C3a is a strongly basic 77 residue protein with a molecular mass of approximately 10 kDa[1]. Residues 17-66 are made up of three disulfide bonds that confer stability and three anti-parallel helices. The N-terminus is comprised of a fourth flexible helical structure, while the C terminus is disordered[2]. C3a has a regulatory process and a structure homologous to complement component C5a, with which it shares 36% of its sequence identity[3].
C3a Receptor[edit]
C3a induces an immunological response through a 482 residue G-protein-coupled receptor called C3aR. The C3aR is similarly structurally homologous to C5aR, but contains an extracellular domain with more than 160 amino acids[4]. 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 large loop, is required for C3a binding[5]. It has also been demonstrated that the C3aR N terminus is not required for ligand binding[6].
Formation of C3a[edit]
C3a is formed by 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 opsonization of antigens. Pathogenic infection triggers C3a formation.
Classical Pathway[edit]
The classical pathway of complement activation is initiated when the C1 complex recognizes PAMPs on an anitgen or IgM or IgG antibodies bound to an antigen. The classica pathway is mediated by C1q, which activates C1's proteolytic function, the cleaving of C4 and C2 to effectively form C3-convertase[7].
Lectin Pathway[edit]
The lectin pathway is activated when mannan-binding lectin or ficolins bind to sugars on the antigen. These then form complexes with Mannose-binding lectin-Associated Serine Proteases (MASPs), which have proteolytic activity resulting in C3 convertase formation[8].
Alternative Pathway[edit]
In the alternative pathway of complement activation, C3 spontaneously hydrolyzes into its active form, C3(H2O). This allows C3 to bind to a plasma protein, which is then cleaved to form C3b(H2O)Bb, or fluid-phase C3-convertase. This complex has the ability to catalyze the formation of C3a and C3b after stabilization[9].
Regulation of C3a[edit]
C3a is regulated like other anaphylatoxins,
- ^ Zhou, Wuding (2012-02-01). "The new face of anaphylatoxins in immune regulation". Immunobiology. 217 (2): 225–234. doi:10.1016/j.imbio.2011.07.016. ISSN 1878-3279. PMID 21856033.
- ^ Chang, Jui-Yoa; Lin, Curtis C. -J.; Salamanca, Silvia; Pangburn, Michael K.; Wetsel, Rick A. (2008-12-15). "Denaturation and unfolding of human anaphylatoxin C3a: An unusually low covalent stability of its native disulfide bonds". Archives of Biochemistry and Biophysics. 480 (2): 104–110. doi:10.1016/j.abb.2008.09.013. PMC 2636726. PMID 18854167.
- ^ Bajic, Goran; Yatime, Laure; Klos, Andreas; Andersen, Gregers Rom (2013-02-01). "Human C3a and C3a desArg anaphylatoxins have conserved structures, in contrast to C5a and C5a desArg". Protein Science: A Publication of the Protein Society. 22 (2): 204–212. doi:10.1002/pro.2200. ISSN 1469-896X. PMC 3588916. PMID 23184394.
- ^ Ames, R. S.; Li, Y.; Sarau, H. M.; Nuthulaganti, P.; Foley, J. J.; Ellis, C.; Zeng, Z.; Su, K.; Jurewicz, A. J. (1996-08-23). "Molecular cloning and characterization of the human anaphylatoxin C3a receptor". The Journal of Biological Chemistry. 271 (34): 20231–20234. ISSN 0021-9258. PMID 8702752.
- ^ Gao, Jinming; Choe, Hyeryun; Bota, Dalena; Wright, Paulette L.; Gerard, Craig; Gerard, Norma P. (2003-09-26). "Sulfation of tyrosine 174 in the human C3a receptor is essential for binding of C3a anaphylatoxin". The Journal of Biological Chemistry. 278 (39): 37902–37908. doi:10.1074/jbc.M306061200. ISSN 0021-9258. PMID 12871936.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Crass, T.; Ames, R. S.; Sarau, H. M.; Tornetta, M. A.; Foley, J. J.; Köhl, J.; Klos, A.; Bautsch, W. (1999-03-26). "Chimeric receptors of the human C3a receptor and C5a receptor (CD88)". The Journal of Biological Chemistry. 274 (13): 8367–8370. ISSN 0021-9258. PMID 10085065.
- ^ Arlaud, G. J.; Gaboriaud, C.; Thielens, N. M.; Rossi, V.; Bersch, B.; Hernandez, J. F.; Fontecilla-Camps, J. C. (2001-04-01). "Structural biology of C1: dissection of a complex molecular machinery". Immunological Reviews. 180: 136–145. ISSN 0105-2896. PMID 11414355.
- ^ Degn, Søren E.; Thiel, Steffen; Jensenius, Jens C. (2007-01-01). "New perspectives on mannan-binding lectin-mediated complement activation". Immunobiology. 212 (4–5): 301–311. doi:10.1016/j.imbio.2006.12.004. ISSN 0171-2985. PMID 17544815.
- ^ Merle, Nicolas S.; Church, Sarah Elizabeth; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T. (2015-01-01). "Complement System Part I - Molecular Mechanisms of Activation and Regulation". Frontiers in Immunology. 6: 262. doi:10.3389/fimmu.2015.00262. ISSN 1664-3224. PMC 4451739. PMID 26082779.
{{cite journal}}: CS1 maint: unflagged free DOI (link)