Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface-selective regulation of complement activation.

Autor: Kerr H; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Wong E; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Makou E; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Yang Y; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Marchbank K; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Kavanagh D; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Richards A; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Herbert AP; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom., Barlow PN; From the Schools of Chemistry and Biological Sciences, Joseph Black Building, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, Scotland, United Kingdom Paul.Barlow@ed.ac.uk.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2017 Aug 11; Vol. 292 (32), pp. 13345-13360. Date of Electronic Publication: 2017 Jun 21.
DOI: 10.1074/jbc.M117.795088
Abstrakt: Spontaneous activation enables the complement system to respond very rapidly to diverse threats. This activation is efficiently suppressed by complement factor H (CFH) on self-surfaces but not on foreign surfaces. The surface selectivity of CFH, a soluble protein containing 20 complement-control protein modules (CCPs 1-20), may be compromised by disease-linked mutations. However, which of the several functions of CFH drives this self-surface selectivity remains unknown. To address this, we expressed human CFH mutants in Pichia pastoris We found that recombinant I62-CFH (protective against age-related macular degeneration) and V62-CFH functioned equivalently, matching or outperforming plasma-derived CFH, whereas R53H-CFH, linked to atypical hemolytic uremic syndrome (aHUS), was defective in C3bBb decay-accelerating activity (DAA) and factor I cofactor activity (CA). The aHUS-linked CCP 19 mutant D1119G-CFH had virtually no CA on (self-like) sheep erythrocytes ( E S ) but retained DAA. The aHUS-linked CCP 20 mutant S1191L/V1197A-CFH (LA-CFH) had dramatically reduced CA on E S but was less compromised in DAA. D1119G-CFH and LA-CFH both performed poorly at preventing complement-mediated hemolysis of E S PspCN, a CFH-binding Streptococcus pneumoniae protein domain, binds CFH tightly and increases accessibility of CCPs 19 and 20. PspCN did not improve the DAA of any CFH variant on E S Conversely, PspCN boosted the CA, on E S , of I62-CFH, R53H-CFH, and LA-CFH and also enhanced hemolysis protection by I62-CFH and LA-CFH. We conclude that CCPs 19 and 20 are critical for efficient CA on self-surfaces but less important for DAA. Exposing CCPs 19 and 20 with PspCN and thus enhancing CA on self-surfaces may reverse deficiencies of some CFH variants.
(© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze: MEDLINE
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