The factor H variant associated with age-related macular degeneration (H384) and the non-disease associated form bind differentially to C-reactive protein, fibromodulin, DNA and necrotic cells.
Holmér, Andreas LU ; Trouw, Leendert LU ; Clark, Simon J ; Sjolander, Jonatan ; Heinegård, Dick LU ; Sim, Robert B ; Day, Anthony J and Blom, Anna LU
(2007)
In Journal of Biological Chemistry
282(15).
p.10894-10900
- Abstract
- Recently, a polymorphism in the complement regulator factor H (FH) gene has been associated with age-related macular degeneration. When histidine instead of tyrosine is present at position 384 in the seventh complement control protein (CCP) domain of FH, the risk for age-related macular degeneration is increased. It was recently shown that these allotypic variants of FH, in the context of a recombinant construct corresponding to CCPs 6 - 8, recognize polyanionic structures differently, which may lead to altered regulation of the alternative pathway of complement. We show now that His-384, corresponding to the risk allele, binds C-reactive protein (CRP) poorly compared with the Tyr-384 form. We also found that C1q and phosphorylcholine do... (More)
- Recently, a polymorphism in the complement regulator factor H (FH) gene has been associated with age-related macular degeneration. When histidine instead of tyrosine is present at position 384 in the seventh complement control protein (CCP) domain of FH, the risk for age-related macular degeneration is increased. It was recently shown that these allotypic variants of FH, in the context of a recombinant construct corresponding to CCPs 6 - 8, recognize polyanionic structures differently, which may lead to altered regulation of the alternative pathway of complement. We show now that His-384, corresponding to the risk allele, binds C-reactive protein (CRP) poorly compared with the Tyr-384 form. We also found that C1q and phosphorylcholine do not compete with FH for binding to C-reactive protein. The interaction with extracellular matrix protein fibromodulin, which we now show to be mediated, at least in part, by CCP6 - 8 of FH, occurs via the polypeptide of fibromodulin and not through its glycosaminoglycan modifications. The Tyr-384 variant of FH bound fibromodulin better than the His-384 form. Furthermore, we find that CCP6 - 8 is able to interact with DNA and necrotic cells, but in contrast the His-384 allotype binds these ligands more strongly than the Tyr-384 variant. The variations in binding affinity of the two alleles indicate that complement activation and local inflammation in response to different targets will differ between His/His and Tyr/Tyr homozygotes. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/165759
- author
- Holmér, Andreas
LU
; Trouw, Leendert
LU
; Clark, Simon J
; Sjolander, Jonatan
; Heinegård, Dick
LU
; Sim, Robert B
; Day, Anthony J
and Blom, Anna
LU
- organization
- publishing date
- 2007
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 282
- issue
- 15
- pages
- 10894 - 10900
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000245941500008
- scopus:34249740145
- pmid:17293598
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M610256200
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Protein Chemistry (013017510), Clinical Chemistry, Malmö (013016000), Department of Experimental Medical Science (013210000), Connective Tissue Biology (013230151)
- id
- f6b3225e-a46b-4c04-91ca-353518f7feb2 (old id 165759)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17293598&dopt=Abstract
- date added to LUP
- 2016-04-01 12:01:50
- date last changed
- 2022-03-20 22:28:20
@article{f6b3225e-a46b-4c04-91ca-353518f7feb2,
abstract = {{Recently, a polymorphism in the complement regulator factor H (FH) gene has been associated with age-related macular degeneration. When histidine instead of tyrosine is present at position 384 in the seventh complement control protein (CCP) domain of FH, the risk for age-related macular degeneration is increased. It was recently shown that these allotypic variants of FH, in the context of a recombinant construct corresponding to CCPs 6 - 8, recognize polyanionic structures differently, which may lead to altered regulation of the alternative pathway of complement. We show now that His-384, corresponding to the risk allele, binds C-reactive protein (CRP) poorly compared with the Tyr-384 form. We also found that C1q and phosphorylcholine do not compete with FH for binding to C-reactive protein. The interaction with extracellular matrix protein fibromodulin, which we now show to be mediated, at least in part, by CCP6 - 8 of FH, occurs via the polypeptide of fibromodulin and not through its glycosaminoglycan modifications. The Tyr-384 variant of FH bound fibromodulin better than the His-384 form. Furthermore, we find that CCP6 - 8 is able to interact with DNA and necrotic cells, but in contrast the His-384 allotype binds these ligands more strongly than the Tyr-384 variant. The variations in binding affinity of the two alleles indicate that complement activation and local inflammation in response to different targets will differ between His/His and Tyr/Tyr homozygotes.}},
author = {{Holmér, Andreas and Trouw, Leendert and Clark, Simon J and Sjolander, Jonatan and Heinegård, Dick and Sim, Robert B and Day, Anthony J and Blom, Anna}},
issn = {{1083-351X}},
language = {{eng}},
number = {{15}},
pages = {{10894--10900}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{The factor H variant associated with age-related macular degeneration (H384) and the non-disease associated form bind differentially to C-reactive protein, fibromodulin, DNA and necrotic cells.}},
url = {{http://dx.doi.org/10.1074/jbc.M610256200}},
doi = {{10.1074/jbc.M610256200}},
volume = {{282}},
year = {{2007}},
}