Back to Search
Start Over
Mechanistic insights into complement pathway inhibition by CR1 domain duplication.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107451. Date of Electronic Publication: 2024 Jun 04. - Publication Year :
- 2024
-
Abstract
- Complement receptor 1 (CR1) is a membrane glycoprotein with a highly duplicated domain structure able to bind multiple ligands such as C3b and C4b, the activated fragments of complement components C3 and C4, respectively. We have previously used our knowledge of this domain structure to identify CSL040, a soluble extracellular fragment of CR1 containing the long homologous repeat (LHR) domains A, B, and C. CSL040 retains the ability to bind both C3b and C4b but is also a more potent complement inhibitor than other recombinant CR1-based therapeutics. To generate soluble CR1 variants with increased inhibitory potential across all three complement pathways, or variants with activity skewed to specific pathways, we exploited the domain structure of CR1 further by generating LHR domain duplications. We identified LHR-ABCC, a soluble CR1 variant containing a duplicated C3b-binding C-terminal LHR-C domain that exhibited significantly enhanced alternative pathway inhibitory activity in vitro compared to CSL040. Another variant, LHR-BBCC, containing duplications of both LHR-B and LHR-C with four C3b binding sites, was shown to have reduced classical/lectin pathway inhibitory activity compared to CSL040, but comparable alternative pathway activity. Interestingly, multiplication of the C4b-binding LHR-A domain resulted in only minor increases in classical/lectin pathway inhibitory activity. The CR1 duplication variants characterized in these in vitro potency assays, as well as in affinity in solution C3b and C4b binding assays, not only provides an opportunity to identify new therapeutic molecules but also additional mechanistic insights to the multiple interactions between CR1 and C3b/C4b.<br />Competing Interests: Conflict of interest S. W., A. B. M., T. R., and M. P. H. are listed as inventors on International Patent Publication number WO2019/218009. All authors are CSL shareholders.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Receptors, Complement 3b metabolism
Receptors, Complement 3b genetics
Receptors, Complement 3b chemistry
Complement C4b metabolism
Complement C4b genetics
Complement C4b chemistry
Protein Binding
Protein Domains
Complement C3b metabolism
Complement C3b chemistry
Complement C3b genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 300
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38844131
- Full Text :
- https://doi.org/10.1016/j.jbc.2024.107451