Cargando…

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

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 pro...

Descripción completa

Detalles Bibliográficos
Autores principales: Kerr, Heather, Wong, Edwin, Makou, Elisavet, Yang, Yi, Marchbank, Kevin, Kavanagh, David, Richards, Anna, Herbert, Andrew P., Barlow, Paul N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555194/
https://www.ncbi.nlm.nih.gov/pubmed/28637873
http://dx.doi.org/10.1074/jbc.M117.795088
_version_ 1783256895610421248
author Kerr, Heather
Wong, Edwin
Makou, Elisavet
Yang, Yi
Marchbank, Kevin
Kavanagh, David
Richards, Anna
Herbert, Andrew P.
Barlow, Paul N.
author_facet Kerr, Heather
Wong, Edwin
Makou, Elisavet
Yang, Yi
Marchbank, Kevin
Kavanagh, David
Richards, Anna
Herbert, Andrew P.
Barlow, Paul N.
author_sort Kerr, Heather
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5555194
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher American Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-55551942017-08-16 Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation Kerr, Heather Wong, Edwin Makou, Elisavet Yang, Yi Marchbank, Kevin Kavanagh, David Richards, Anna Herbert, Andrew P. Barlow, Paul N. J Biol Chem Immunology 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. American Society for Biochemistry and Molecular Biology 2017-08-11 2017-06-21 /pmc/articles/PMC5555194/ /pubmed/28637873 http://dx.doi.org/10.1074/jbc.M117.795088 Text en © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Immunology
Kerr, Heather
Wong, Edwin
Makou, Elisavet
Yang, Yi
Marchbank, Kevin
Kavanagh, David
Richards, Anna
Herbert, Andrew P.
Barlow, Paul N.
Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation
title Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation
title_full Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation
title_fullStr Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation
title_full_unstemmed Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation
title_short Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation
title_sort disease-linked mutations in factor h reveal pivotal role of cofactor activity in self-surface–selective regulation of complement activation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555194/
https://www.ncbi.nlm.nih.gov/pubmed/28637873
http://dx.doi.org/10.1074/jbc.M117.795088
work_keys_str_mv AT kerrheather diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT wongedwin diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT makouelisavet diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT yangyi diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT marchbankkevin diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT kavanaghdavid diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT richardsanna diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT herbertandrewp diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation
AT barlowpauln diseaselinkedmutationsinfactorhrevealpivotalroleofcofactoractivityinselfsurfaceselectiveregulationofcomplementactivation