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Common evolutionary origin of alpha 2-macroglobulin and complement components C3 and C4
Abstract:
A comparison of the sequence of the subunit of human alpha 2-macroglobulin (alpha 2M; 1451 amino acid residues) with that of murine complement component pro-C3 (1639 amino acid residues) reveals eight extended regions of sequence similarity. These regions contain between 19% and 31% identically placed residues and account for 75% and 67%, respectively, of the polypeptide chains of alpha 2M and pro-C3. Published sequence data for complement component C4 show that segments of this protein match well with corresponding stretches in alpha 2M and pro-C3. It is proposed that alpha 2M, C3 and C4, which all contain a unique activatable beta-cysteinyl-gamma-glutamyl thiol ester, have a common evolutionary origin and are homologous proteins. Several larger regions of low sequence similarity indicate the presence of structural domains in each of these proteins that specifically modify an underlying common gross structure. The quartets of basic residues in pro-C3 and pro-C4, at which cleavage takes place to produce the mature subunits of these proteins, and most of the residues forming the anaphylatoxin peptides of C3 and C4 (C3a and C4a) are absent in alpha 2M. In addition, C3 and C4 contain large portions, which extend beyond the COOH terminus of alpha 2M.
Insights
Human alpha-2-macroglobulin (alpha 2M) and complement proteins C3 and C4 share sequence similarities, suggesting a common evolutionary origin. These homologous proteins possess distinct structural domains and functional differences.
Area of Science:
- Biochemistry
- Molecular Biology
- Evolutionary Biology
Background:
- Alpha-2-macroglobulin (alpha 2M) is a large plasma protein involved in immune regulation.
- Complement components C3 and C4 are key proteins in the complement system, crucial for innate immunity.
Purpose of the Study:
- To investigate the evolutionary relationship between alpha 2M and complement proteins C3 and C4.
- To identify sequence similarities and structural domains shared among these proteins.
Main Methods:
- Comparative sequence analysis of human alpha 2M and murine pro-C3.
- Examination of published sequence data for human complement component C4.
Main Results:
- Eight extended regions of sequence similarity were identified between alpha 2M and pro-C3, with 19-31% identical residues.
- Significant sequence matches were also observed between alpha 2M, pro-C3, and C4, indicating homology.
- Structural domains were inferred, suggesting modifications to a common underlying structure.
Conclusions:
- Alpha 2M, C3, and C4 are proposed to be homologous proteins with a common evolutionary origin due to shared sequence similarities and the presence of a unique thiol ester.
- Differences in specific residues and structural extensions highlight functional divergences among these proteins.