Structural basis for complement factor H linked age-related macular degeneration
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Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to ∼50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance–monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG–FH complex.
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The reduction in HSPGs may exacerbate the effect of the FH p.Y402H polymorphism because the variant protein binds less well to HSPGs than the wild-type protein.
“This may exacerbate the effect of the FH p.Y402H polymorphism (a major genetic risk factor for AMD) as it has been proposed that the variant protein binds less well to HSPGs than the wild-type protein [56,57].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [57]
Heparan sulphate proteoglycans (HSPGs), key binders of complement regulator Factor H (FH), are reduced with age and may lead to increased complement activation.
“However, heparan sulphate proteoglycans (HSPGs), key binders of the complement regulator Factor H (FH), have been shown to be reduced with age [55] and may lead to increased complement activation [56,57].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [57]
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The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147 · see citing works
Complement factor H polymorphism in age-related macular degeneration
Klein, R. J., Zeiss, C., Chew, E. Y., Tsai, J.-Y., Sackler, R. S., Haynes, C., Henning, A. K., SanGiovanni, J. P., Mane, S. M., Mayne, S. T., et al. (2005) · Science · doi:10.1126/science.1109557 · Cited by 4,492 · see citing works
Prevalence of Age-Related Macular Degeneration in the United States
The Eye Diseases Prevalence Research Group* (2004) · Archives of Ophthalmology · doi:10.1001/archopht.122.4.564 · Cited by 2,742 · see citing works
Complement factor H polymorphism and age-related macular degeneration
Edwards, A. O., Ritter, R., Abel, K. J., Manning, A., Panhuysen, C., & Farrer, L. A. (2005) · Science · doi:10.1126/science.1110189 · Cited by 2,449 · see citing works
Complement factor H variant increases the risk of age-related macular degeneration
Haines, J. L., Hauser, M. A., Schmidt, S., Scott, W. K., Olson, L. M., Gallins, P., Spencer, K. L., Kwan, S. Y., Noureddine, M., Gilbert, J. R., et al. (2005) · Science · doi:10.1126/science.1110359 · Cited by 2,424 · see citing works
Hageman, G. S., Anderson, D. H., Johnson, L. V., Hancox, L. S., Taiber, A. J., Hardisty, L. I., Hageman, J. L., Stockman, H. A., Borchardt, J. D., Gehrs, K. M., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501536102 · Cited by 1,961 · see citing works
Modulation of the alternative complement pathways by beta 1 H globulin.
Whaley, K., & Ruddy, S. (1976) · The Journal of Experimental Medicine · doi:10.1084/jem.144.5.1147 · Cited by 584 · see citing works
Control of the amplification convertase of complement by the plasma protein beta1H.
Weiler, J. M., Daha, M. R., Austen, K. F., & Fearon, D. T. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.9.3268 · Cited by 570 · see citing works
Fearon, D. T. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.4.1971 · Cited by 418 · see citing works
N.m.r. and molecular-modelling studies of the solution conformation of heparin
Mulloy, B., Forster, M. J., Jones, C., & Davies, D. B. (1993) · Biochemical Journal · doi:10.1042/bj2930849 · Cited by 410 · see citing works
Kazatchkine, M. D., Fearon, D. T., & Kf, A. (1979) · PubMed · Cited by 350 · see citing works
The complete amino acid sequence of human complement factor H
Ripoche, J., Day, A. J., Harris, T. J. R., & Sim, R. B. (1988) · Biochemical Journal · doi:10.1042/bj2490593 · Cited by 348 · see citing works
Self-citationKazatchkine, M. D., Fearon, D. T., & Austen, K. F. (1979) · The Journal of Immunology · doi:10.4049/jimmunol.122.1.75 · Cited by 290 · see citing works
Detection of Protein Assemblies in Crystals
Krissinel, E., & Henrick, K. (2005) · Lecture notes in computer science · doi:10.1007/11560500_15 · Cited by 253 · see citing works
Identification of the Second Heparin-Binding Domain in Human Complement Factor H
Blackmore, T., Hellwage, J., Sadlon, T. A., Higgs, N., Zipfel, P. F., Ward, H. M., & Gordon, D. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.7.3342 · Cited by 222 · see citing works
Solution Structure of a Pair of Complement Modules by Nuclear Magnetic Resonance
Barlow, P. N., Steinkasserer, A., Norman, D. G., Kieffer, B., Wiles, A. P., Sim, R. B., & Campbell, I. D. (1993) · Journal of Molecular Biology · doi:10.1006/jmbi.1993.1381 · Cited by 204 · see citing works
Self-citationDefective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration
Skerka, C., Lauer, N., Weinberger, A. A. W. A., Keilhauer, C. N., Sühnel, J., Smith, R., Schlötzer–Schrehardt, U., Fritsche, L., Heinen, S., & Hartmann, A. (2007) · Molecular Immunology · doi:10.1016/j.molimm.2007.02.012 · Cited by 197 · see citing works
Blackmore, T., Sadlon, T. A., Ward, H. M., Lublin, D. M., & Gordon, D. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.12.5422 · Cited by 195 · see citing works
Localization of the heparin-binding site on complement factor H.
Pangburn, M. K., Atkinson, M. A., & Meri, S. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55379-5 · Cited by 190 · see citing works
Clark, S. J., Higman, V. A., Mulloy, B., Perkins, S. J., Lea, S. M., Sim, R. B., & Day, A. J. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605083200 · Cited by 185 · see citing works
Self-citationGiannakis, E., Jokiranta, T. S., Male, D. A., Ranganathan, S., Ormsby, R. J., Fischetti, V. A., Mold, C., & Gordon, D. L. (2003) · European Journal of Immunology · doi:10.1002/eji.200323541 · Cited by 166 · see citing works
Jokiranta, T. S., Jaakola, V., Lehtinen, M. J., Pärepalo, M., Meri, S., & Goldman, A. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601052 · Cited by 156 · see citing works
Sjöberg, A. P., Trouw, L. A., Clark, S. J., Sjölander, J., Heinegård, D. K., Sim, R. B., Day, A. J., & Blom, A. M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610256200 · Cited by 142 · see citing works
Self-citationHerbert, A. P., Deakin, J. A., Schmidt, C. Q., Blaum, B. S., Egan, C. L., Ferreira, V. P., Pangburn, M. K., Lyon, M., Uhrı́n, D., & Barlow, P. N. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609636200 · Cited by 115 · see citing works
Self-citationBarlow, P. N., Norman, D. G., Steinkasserer, A., Horne, T. J., Pearce, J., Driscoll, P. C., Sim, R. B., & Campbell, I. D. (1992) · Biochemistry · doi:10.1021/bi00129a011 · Cited by 110 · see citing works
Self-citationHerbert, A. P., Uhrı́n, D., Lyon, M., Pangburn, M. K., & Barlow, P. N. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513611200 · Cited by 89 · see citing works
Self-citationStructural insights into the central complement component C3
Janssen, B. J. C., & Gros, P. (2006) · Molecular Immunology · doi:10.1016/j.molimm.2006.06.017 · Cited by 80 · see citing works
Localization of the third heparin-binding site in the human complement regulator factor H1
Ormsby, R. J., Jokiranta, T. S., Duthy, T. G., Griggs, K. M., Sadlon, T. A., Giannakis, E., & Gordon, D. (2005) · Molecular Immunology · doi:10.1016/j.molimm.2005.09.012 · Cited by 71 · see citing works
Sequence polymorphism of human complement factor H
Day, A. J., Willis, A. C., Ripoche, J., & Sim, R. B. (1988) · Immunogenetics · doi:10.1007/bf00346588 · Cited by 53 · see citing works
Self-citationVerdugo, M. E., & Ray, J. (1997) · Experimental Eye Research · doi:10.1006/exer.1997.0325 · Cited by 27 · see citing works
Prosser, B. E., Johnson, S., Roversi, P., Clark, S. J., Tarelli, E., Sim, R. B., Day, A. J., & Lea, S. M. (2007) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309107020052 · Cited by 16 · see citing works
Self-citationConformational Complexity of Complement Component C3
Janssen, B. J. C., & Gros, P. (2007) · Springer eBooks · doi:10.1007/0-387-34134-x_20 · Cited by 10 · see citing works
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- [24]Pangburn, M.K., M.A. Atkinson, and S. Meri. 1991. Localization of the heparin-binding site on complement factor H. J. Biol. Chem. 266: 16847–16853. 1832158
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Merle, N. S., Church, S. E., Fremeaux-Bacchi, V., & Roumenina, L. T. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00262 · Cited by 1,620 · see citing works
Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait
Wright, A. F., Chakarova, C. F., El-Aziz, M. M. A., & Bhattacharya, S. S. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2717 · Cited by 632 · see citing works
“In most cases, the causal variant or variants have not been identified, although there are some strong candidate”
Complement activation, regulation, and molecular basis for complement‐related diseases
Bajic, G., Degn, S. E., Thiel, S., & Andersen, G. R. (2015) · The EMBO Journal · doi:10.15252/embj.201591881 · Cited by 374 · see citing works
“The crystal structure of FH CCP6–8 402H variant in complex with a sulfated sugar as a GAG model has suggested how this FH mutation contributes to AMD pathogenesis (Prosser et al , 2007) (Fig 5D).”
Pharmacology of Heparin and Related Drugs
Mulloy, B., Hogwood, J., Gray, E., Lever, R., & Page, C. P. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.011247 · Cited by 341 · see citing works
“It is known that mutations at or near the heparin binding site in CFH CCP 6–8 can predispose to agerelated macular degeneration (Prosser et al., 2007), and that mutations at or near the CCP 19–20 site are associated with atypical hemolytic uremic syndrome (Józsi et al., 2006).”
BackgroundWu, J., Wu, Y., Ricklin, D., Janssen, B. J. C., Lambris, J. D., & Gros, P. (2009) · Nature Immunology · doi:10.1038/ni.1755 · Cited by 327 · see citing works
“Furthermore, FH may be recruited to host membranes by recognizing and binding self components, such as glycosaminoglycans, and thereby may prevent the opsonization of host tissue with low surface expression of RC”
Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates
Schneider, M. C., Prosser, B. E., Caesar, J. J. E., Kugelberg, E., Li, S., Zhang, Q., Quoraishi, S., Lovett, J. E., Deane, J. E., Sim, R. B., et al. (2009) · Nature · doi:10.1038/nature07769 · Cited by 314 · see citing works
Self-citationde Córdoba, S. R., & de Jorge, E. G. (2007) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2007.03552.x · Cited by 287 · see citing works
Structural basis for sialic acid–mediated self-recognition by complement factor H
Blaum, B. S., Hannan, J. P., Herbert, A. P., Kavanagh, D., Uhrín, D., & Stehle, T. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1696 · Cited by 278 · see citing works
Self-citationThe complement system in age-related macular degeneration
Armento, A., Ueffing, M., & Clark, S. J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03796-9 · Cited by 258 · see citing works
Self-citationBoyer, D. S., Schmidt-Erfurth, U. M., Campagne, M. V. L., Henry, E. C., & Brittain, C. J. (2016) · Retina · doi:10.1097/iae.0000000000001392 · Cited by 263 · see citing works
Aging is not a disease: Distinguishing age-related macular degeneration from aging
Ardeljan, D., & Chan, C. (2013) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2013.07.003 · Cited by 243 · see citing works
“CFH functions as a complement inhibitor, preventing activation of the alternative pathway via recognition and binding of heparin on cell surfaces as well as blocking alternative activation via C-reactive protein (CRP) in response to tissue injury (Alsenz et al., 1985; Ferreira et al., 2010; Prosser et al., 2007).”
BackgroundStructural basis for engagement by complement factor H of C3b on a self surface
Morgan, H. P., Schmidt, C. Q., Guariento, M., Blaum, B. S., Gillespie, D., Herbert, A. P., Kavanagh, D., Mertens, H. D. T., Svergun, D. I., Johansson, C. M., et al. (2011) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2018 · Cited by 239 · see citing works
“By manually concatenating our SAXS-derived envelopes for FH8–15 and FH15–19 with the X-ray derived structures of FH6–8 36 and C3d:FH19–20 it was possible to model FH modules 6–20 in complex with C3b (Fig.”
Self-citationZhao, J., Wu, H. M., Khosravi, M., Cui, H., Qian, X., Kelly, J. A., Kaufman, K. M., Langefeld, C. D., Williams, A. H., Comeau, M. E., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002079 · Cited by 232 · see citing works
“Y402H (rs1061170) is the most studied non-synonymous SNP of CFH. Y402H is located in SCR7 and affects the binding of CFH with glycosaminoglycans and CRP [22,23,24].”
BackgroundHeurich, M., Martínez‐Barricarte, R., Francis, N., Roberts, D. L., de Córdoba, S. R., Morgan, B. P., & Harris, C. L. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019338108 · Cited by 230 · see citing works
“The fH402H risk variant had no direct effect on fH AP regulation but influenced binding to sialylated surfaces (27, 28).”
BackgroundProtection of host cells by complement regulators
Schmidt, C. Q., Lambris, J. D., & Ricklin, D. (2016) · Immunological Reviews · doi:10.1111/imr.12475 · Cited by 211 · see citing works
Orth‐Höller, D., Khan, A. B., Naim, A., Grif, K., Brockmeyer, J., Karch, H., Joannidis, M., Clark, S. J., Day, A. J., Fidanzi, S., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900151 · Cited by 208 · see citing works
“The 402H allele has been reported to be associated with a higher probability of acquiring agerelated macular degeneration (13) and has different ligand-binding properties when compared with the nondisease-associated 402Y variant (12, 14).”
BackgroundSelf-citationA New Map of Glycosaminoglycan and C3b Binding Sites on Factor H
Schmidt, C. Q., Herbert, A. P., Kavanagh, D., Gandy, C., Fenton, C. J., Blaum, B. S., Lyon, M., Uhrı́n, D., & Barlow, P. N. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2610 · Cited by 208 · see citing works
“The triple module fH 6–8 was also used as a positive control on GMSA since its ability to bind heparin had been previously well characterized (19, 29).”
BackgroundMethodSelf-citationComplement factor H in host defense and immune evasion
Parente, R., Clark, S. J., Inforzato, A., & Day, A. J. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2418-4 · Cited by 193 · see citing works
“It is unusual that a single amino acid change has such a pronounced effect on HS binding but structural studies (involving NMR analysis and crystallography) indicate that the two FH variants likely use a different mode of interaction (see [45, 53]); evidence suggests that the histidine-402 can interact directly with a…”
BackgroundInfluentialSelf-citationClark, S. J., Perveen, R., Hakobyan, S., Morgan, B. P., Sim, R. B., Bishop, P. N., & Day, A. J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.103986 · Cited by 188 · see citing works
Self-citationOxidative Stress Renders Retinal Pigment Epithelial Cells Susceptible to Complement-mediated Injury
Thurman, J. M., Renner, B., Kunchithapautham, K., Ferreira, V. P., Pangburn, M. K., Ablonczy, Z., Tomlinson, S., Holers, V. M., & Rohrer, B. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808166200 · Cited by 186 · see citing works
Ferreira, V. P., Herbert, A. P., Cortés, C., Mckee, K., Blaum, B. S., Esswein, S. T., Uhrı́n, D., Barlow, P. N., Pangburn, M. K., & Kavanagh, D. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804031 · Cited by 173 · see citing works
“CCP 7 and CCP 20) interact with heparin and other polyanions (24-30).”
BackgroundSelf-citationKlein, M. L., Francis, P. J., Rosner, B., Reynolds, R., Hamon, S. C., Schultz, D. W., Ott, J., & Seddon, J. M. (2008) · Ophthalmology · doi:10.1016/j.ophtha.2008.01.036 · Cited by 172 · see citing works
Mediators of ocular angiogenesis
Qazi, Y., Maddula, S., & Ambati, B. K. (2009) · Journal of Genetics · doi:10.1007/s12041-009-0068-0 · Cited by 173 · see citing works
Immunopathological aspects of age-related macular degeneration
Patel, M. M., & Chan, C. (2008) · Seminars in Immunopathology · doi:10.1007/s00281-008-0112-9 · Cited by 163 · see citing works
“It also binds C-reactive protein (CRP) to inhibit CRP-mediated activation of the alternate pathway in response to damaged tissue [26, 27].”
BackgroundThe complotype: dictating risk for inflammation and infection
Harris, C. L., Heurich, M., de Córdoba, S. R., & Morgan, B. P. (2012) · Trends in Immunology · doi:10.1016/j.it.2012.06.001 · Cited by 162 · see citing works
Complement factor H in AMD: Bridging genetic associations and pathobiology
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“Crystal structure and mutation analyses of recombinant fragments of CFH suggest that the CFH H402 amino acid is involved in HS binding in a more complex manner than what was initially assumed (Prosser et al., 2007).”
BackgroundFactor H: A Complement Regulator in Health and Disease, and a Mediator of Cellular Interactions
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“Since residue 402 in SCR7 is involved in the glycosaminoglycan-binding site of factor H, there are also subtle differences between the variants in their interaction with heparin and glycosaminoglycan-analogs [97,99,100].”
BackgroundRohrer, B., Long, Q., Coughlin, B., Wilson, R. B., Huang, Y., Qiao, F., Tang, P. H., Kunchithapautham, K., Gilkeson, G. S., & Tomlinson, S. (2009) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.08-2222 · Cited by 154 · see citing works
“Y402H in fH lies at the center of a major binding site in SCR7.(10) It has been suggested that this mutation may alter the interaction of fH with target surface polyanions, particularly glycosaminoglycan heparin-sulfate,(10,11) and may reduce its binding affinity to surface-attached C-reactive protein,(12) although re…”
BackgroundRegulation of age-related macular degeneration-like pathology by complement factor H
Toomey, C. B., Kelly, U., Saban, D. R., & Rickman, C. B. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1424391112 · Cited by 156 · see citing works
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Roumenina, L. T., Loirat, C., Dragon‐Durey, M., Halbwachs‐Mecarelli, L., Sautès‐Fridman, C., & Frémeaux‐Bacchi, V. (2011) · Journal of Immunological Methods · doi:10.1016/j.jim.2010.12.020 · Cited by 150 · see citing works
Clark, S. J., Ridge, L. A., Herbert, A. P., Hakobyan, S., Mulloy, B., Lennon, R., Würzner, R., Morgan, B. P., Uhrı́n, D., Bishop, P. N., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1201751 · Cited by 148 · see citing works
Self-citationHecker, L. A., Edwards, A. O., Ryu, E., Tosakulwong, N., Baratz, K. H., Brown, W. L., Issa, P. C., Scholl, H. P. N., Pollok‐Kopp, B., Schmid‐Kubista, K. E., et al. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp472 · Cited by 147 · see citing works
“This concept is consistent with the demonstrated alteration in binding of fH402H protein to cell surfaces and polyanions (32).”
ResultSchmidt, C. Q., Herbert, A. P., Hocking, H. G., Uhrı́n, D., & Barlow, P. N. (2007) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2007.03553.x · Cited by 135 · see citing works
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Serruto, D., Rappuoli, R., Scarselli, M., Gros, P., & van Strijp, J. A. G. (2010) · Nature Reviews Microbiology · doi:10.1038/nrmicro2366 · Cited by 128 · see citing works
“Recognition of host cells and surfaces by factor H can be attributed to the binding of polyanions such as glycosaminoglycans by domains CCP6–CCP8 and by the C-terminal domains CCP19–CCP20 (these C-terminal domains form a ternary complex with both surface glycans and the TED domain of C3b”
BackgroundAge-related macular degeneration and the role of the complement system
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Self-citationClark, S. J., Schmidt, C. Q., White, A. M., Hakobyan, S., Morgan, B. P., & Bishop, P. N. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1401613 · Cited by 122 · see citing works
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Makou, E., Herbert, A. P., & Barlow, P. N. (2013) · Biochemistry · doi:10.1021/bi4003452 · Cited by 115 · see citing works
Self-citationInforzato, A., Baldock, C., Jowitt, T. A., Holmes, D. F., Lindstedt, R., Marcellini, M., Rivieccio, V., Briggs, D. C., Kadler, K. E., Verdoliva, A., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.085639 · Cited by 113 · see citing works
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Ufret-Vincenty, R. L., Aredo, B., Liu, X., McMahon, A., Chen, P. W., Sun, H., Niederkorn, J. Y., & Kędzierski, W. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-4457 · Cited by 104 · see citing works
“This has been confirmed by recent crystallography studies.(36) Because the main source of Cfh is the liver, we chose to express the Cfh transgenes using a promoter of human ApoE which is constitutively expressed in the liver.”
BackgroundZipfel, P. F., Lauer, N., & Skerka, C. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-5635-4_2 · Cited by 99 · see citing works
“This differences in binding are explained by the alteration of the distribution of positively charged amino acids by the H402 which are essential for a proper heparin binding over SCR 7 (Prosser et al. 2007; Ormsby et al. 2008).”
BackgroundWu, Y., Qu, H., Sfyroera, G., Τζέκου, Α., Kay, B. K., Nilsson, B., Ekdahl, K. N., Ricklin, D., & Lambris, J. D. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003802 · Cited by 97 · see citing works
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Pangburn, M. K., Ferreira, V. P., & Cortés, C. (2008) · Vaccine · doi:10.1016/j.vaccine.2008.11.023 · Cited by 94 · see citing works
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Boon, C. J. F., van de Kar, N. C. A. J., Klevering, B. J., KEUNEN, J. E. E., Cremers, F. P. M., Klaver, C. C. W., Hoyng, C. B., Daha, M. R., & den Hollander, A. I. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.02.013 · Cited by 91 · see citing works
Developments in anti-complement therapy; from disease to clinical trial
Harris, C. L., Pouw, R. B., Kavanagh, D., Sun, R., & Ricklin, D. (2018) · Molecular Immunology · doi:10.1016/j.molimm.2018.06.008 · Cited by 93 · see citing works
Complement factor H binds to denatured rather than to native pentameric C-reactive protein
Hakobyan, S., Harris, C. L., van den Berg, C. W., Fernandez-Alonso, M. C., de Jorge, E. G., de Cordoba, S. R., Rivas, G., Mangione, P., Pepys, M. B., & Morgan, B. P. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803648200 · Cited by 90 · see citing works
Ansari, M., McKeigue, P., Skerka, C., Hayward, C., Rudan, I., Vitart, V., Polašek, O., Armbrecht, A.-M., Yates, J. R. W., Vatavuk, Z., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt336 · Cited by 88 · see citing works
Self-citationHijacking Factor H for Complement Immune Evasion
Moore, S. R., Menon, S. S., Cortes, C., & Ferreira, V. P. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.602277 · Cited by 83 · see citing works
Clark, S. J., Bishop, P. N., & Day, A. J. (2010) · Biochemical Society Transactions · doi:10.1042/bst0381342 · Cited by 84 · see citing works
Self-citationMultilocus analysis of age-related macular degeneration
Sawitzke, J., Gold, B., Olsh, A., Schlotterbeck, S., Lemon, K., Visvanathan, K., Allikmets, R. L., & Dean, M. C. (2009) · European Journal of Human Genetics · doi:10.1038/ejhg.2009.23 · Cited by 82 · see citing works
Banda, N. K., Wood, A., Takahashi, K., Levitt, B., Rudd, P. M., Royle, L., Abrahams, J. L., Stahl, G. L., Holers, V. M., & Arend, W. P. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23865 · Cited by 82 · see citing works
Production of biologically active complement factor H in therapeutically useful quantities
Schmidt, C. Q., Slingsby, F., Richards, A., & Barlow, P. N. (2010) · Protein Expression and Purification · doi:10.1016/j.pep.2010.12.002 · Cited by 81 · see citing works
“Protein production based on expression in engineered Escherichia coli, and refolding of insoluble material, has been used for manufacture of several FH fragments [45,46] but not for production of fulllength FH.”
MethodSelf-citationComplementing the sugar code: Role of GAGs and sialic acid in complement regulation
Langford-Smith, A., Day, A. J., Bishop, P. N., & Clark, S. J. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00025 · Cited by 80 · see citing works
“A (1-40) prevents heparanase-catalyzed degradation of heparan sulfate glycosaminoglycans and proteoglycans in vitro.”
BackgroundSelf-citationComplement Factor H–ligand interactions: Self-association, multivalency and dissociation constants
Perkins, S. J., Nan, R., Li, K., Khan, S., & Miller, A. (2011) · Immunobiology · doi:10.1016/j.imbio.2011.10.003 · Cited by 80 · see citing works
“Similar KD ranges are seen also for SCR-19/20 binding to C3d in 137–150 mM NaCl (Table 1).”
BackgroundInfluentialThe Factor H protein family: The switchers of the complement alternative pathway
Lucientes, L., Márquez‐Tirado, B., & de Jorge, E. G. (2022) · Immunological Reviews · doi:10.1111/imr.13166 · Cited by 79 · see citing works
C1, MBL–MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation
Beinrohr, L., Dobó, J., Závodszky, P., & Gál, P. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2008.09.009 · Cited by 78 · see citing works
Rodríguez, E., Rallapalli, P. M., Osborne, A. J., & Perkins, S. J. (2014) · Bioscience Reports · doi:10.1042/bsr20140117 · Cited by 73 · see citing works
Fan, X., Yoshida, Y., Honda, S., Matsumoto, M., Sawada, Y., Hattori, M., Hisanaga, S., Hiwa, R., Nakamura, F., Tomomori, M., et al. (2013) · Molecular Immunology · doi:10.1016/j.molimm.2012.12.006 · Cited by 72 · see citing works
Lewis, L. A., Carter, M. J., & Ram, S. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103748 · Cited by 71 · see citing works
“This construct binds to both fHbp and NspA (14, 34) and further, fH domains 7–8 contain a heparin binding site (35, 36) and can interact weakly with C3b (36).”
BackgroundPechtl, I. C., Kavanagh, D., McIntosh, N., Harris, C. L., & Barlow, P. N. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.211839 · Cited by 70 · see citing works
Self-citationE-selectin ligand complexes adopt an extended high-affinity conformation
Preston, R. C., Jakob, R. P., Binder, F. P. C., Sager, C. P., Ernst, B., & Maier, T. (2015) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjv046 · Cited by 69 · see citing works
Molins, B., Fuentes‐Prior, P., Adán, A., Antón, R. I., Aróstegui, J. I., Yagüe, J., & Dick, A. D. (2016) · Scientific Reports · doi:10.1038/srep22889 · Cited by 69 · see citing works
Keenan, T. D. L., Pickford, C. E., Holley, R. J., Clark, S. J., Lin, W., Dowsey, A. W., Merry, C. L., Day, A. J., & Bishop, P. N. (2014) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.14-14126 · Cited by 65 · see citing works
Self-citationThe role of complement in ocular pathology
Bora, N. S., Jha, P., & Bora, P. S. (2008) · Seminars in Immunopathology · doi:10.1007/s00281-008-0110-y · Cited by 69 · see citing works
“The polymorphism at position 402 in SCR7 reduces the binding affinity to CRP [80] and GAG [81].”
BackgroundMolecular Interactions between Complement Factor H and Its Heparin and Heparan Sulfate Ligands
Perkins, S. J., Fung, K. W., & Khan, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00126 · Cited by 67 · see citing works
“In opposition to these results, the crystal structure of SCR-6/8 His402 bound to a heparin analog suggests that the S-domains bind more strongly to the His402 allotype than to the Tyr402 allotype (53).”
ResultDing, J., Kelly, U., Landowski, M., Toomey, C. B., Groelle, M., Miller, C., Smith, S. G., Klingeborn, M., Singhapricha, T., Jiang, H., et al. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.08.026 · Cited by 65 · see citing works
Electrostatic Interactions Contribute to the Folded-back Conformation of Wild Type Human Factor H
Okemefuna, A. I., Nan, R., Gor, J., & Perkins, S. J. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.06.010 · Cited by 63 · see citing works
“Crystal structures were used for SCR-19/20 (PDB code 2g7i)(21) and SCR-6/8 (PDB code 2uwn).(14) The FH sequence numbering was initiated from the N-terminus of the 18 residue signal peptide, not that of the mature protein.”
Langford-Smith, A., Keenan, T. D. L., Clark, S. J., Bishop, P. N., & Day, A. J. (2013) · Journal of Innate Immunity · doi:10.1159/000356513 · Cited by 62 · see citing works
Self-citationRaychaudhuri, S., Ripke, S., Li, M., Neale, B. M., Fagerness, J. A., Reynolds, R. C., Sobrin, L., Swaroop, A., Abecasis, G. R., Seddon, J. M., et al. (2010) · Nature Genetics · doi:10.1038/ng0710-553 · Cited by 61 · see citing works
Of mice and men: The factor H protein family and complement regulation
Pouw, R. B., Vredevoogd, D. W., Kuijpers, T. W., & Wouters, D. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.03.011 · Cited by 59 · see citing works
“…of different autologous surfaces and consequently the surface omplement regulatory properties of FH (Blackmore et al., 1996; lackmore et al., 1998; Prosser et al., 2007; Schmidt et al., 2008). utations in SCRs 19–20 have been reported to affect sialic acid inding, associated with aHUS (Blaum et…”
BackgroundChirco, K. R., & Potempa, L. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00539 · Cited by 58 · see citing works
“Proc Natl Acad Sci U S A (2005) 102(20):7227–32.”
Exploring multivalent carbohydrate–protein interactions by NMR
Quintana, J. I., Atxabal, U., Unione, L., Ardá, A., & Jiménez‐Barbero, J. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00983h · Cited by 58 · see citing works
Genetics of age-related macular degeneration
Ting, A., Lee, T. K. M., & MacDonald, I. M. (2009) · Current Opinion in Ophthalmology · doi:10.1097/icu.0b013e32832f8016 · Cited by 56 · see citing works
Kandasamy, M., Ying, P. C., Ho, A. W. S., Sumatoh, H., Schlitzer, A., Hughes, T. R., Kemeny, D. M., Morgan, B. P., Ginhoux, F., & Sivasankar, B. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003115 · Cited by 58 · see citing works
“Although complement deficiency is rare in humans, genetic polymorphisms in complement proteins such as factor I, factor B, C3 and factor H are known to affect their availability, activity, and susceptibility to chronic disease conditions [50,51,52,53,54,55,56].”
BackgroundRomero‐Vázquez, S., Llorens, V., Soler-Boronat, A., Figueras‐Roca, M., Adán, A., & Molins, B. (2021) · Biomedicines · doi:10.3390/biomedicines9070763 · Cited by 56 · see citing works
“non‐risk form of FH recognizes a broader range of HS structures, whereas the risk form requires more highly sulfated HS for binding, reducing its ability to interact with HS within the human BrM [106,108].”
BackgroundKelly, U., Yu, L., Kumar, P. P., Ding, J., Jiang, H., Hageman, G. S., Arshavsky, V. Y., Frank, M. M., Hauser, M. A., & Rickman, C. B. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0903596 · Cited by 53 · see citing works
Structural Analysis of the C-Terminal Region (Modules 18–20) of Complement Regulator Factor H (FH)
Morgan, H. P., Mertens, H. D. T., Guariento, M., Schmidt, C. Q., Soares, D. C., Svergun, D. I., Herbert, A. P., Barlow, P. N., & Hannan, J. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032187 · Cited by 53 · see citing works
“Principal GAG (and sialic acid)-binding regions occupy CCPs 6–8 and CCP 20 [13,17,19–24].”
Self-citationPuy, C., Pang, J., Reitsma, S. E., Lorentz, C. U., Tucker, E. I., Gailani, D., Gruber, A., Lupu, F., & McCarty, O. J. T. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2000398 · Cited by 52 · see citing works
“Interestingly, a mutation at CFH Arg341 (R341A) at the end of CCP6 domain, which is the FXIa cleavage site identified in this study, has been associated with age-related macular degeneration perhaps in part due to a reduction in the capacity of the mutant form of CFH to bind heparin (11).”
BackgroundSchmidt, C. Q., Herbert, A. P., Mertens, H. D. T., Guariento, M., Soares, D. C., Uhrı́n, D., Rowe, A. J., Svergun, D. I., & Barlow, P. N. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.10.010 · Cited by 52 · see citing works
Self-citationZhang, Y., Wu, M., Hang, T., Wang, C., Yang, Y., Pan, W., Zang, J., Zhang, M., & Zhang, X. (2017) · Biochemical Journal · doi:10.1042/bcj20170085 · Cited by 52 · see citing works
Haapasalo, K., Jarva, H., Siljander, T., Tewodros, W., Vuopio‐Varkila, J., & Jokiranta, T. S. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06347.x · Cited by 52 · see citing works
“Location of the residue Y402H on crystal structure of domains 6–8 of FH has been reported very recently by Prosser et al. (2007) (PDB entry 2UWN).”
BackgroundStructure of Factor H-binding Protein B (FhbB) of the Periopathogen, Treponema denticola
Miller, D. P., Bell, J. K., McDowell, J. V., Conrad, D. H., Burgner, J. W., Heroux, A., & Marconi, R. T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.339721 · Cited by 49 · see citing works
“SOS is a GAG analog that interacts with a large positively charged groove within CCP6–8 (46).”
BackgroundInfluentialHebecker, M., Okemefuna, A. I., Perkins, S. J., Mihlan, M., Huber-Lang, M. S., & Józsi, M. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.12.005 · Cited by 48 · see citing works
Hammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44 · see citing works
“However, heparan sulphate proteoglycans (HSPGs), key binders of the complement regulator Factor H (FH), have been shown to be reduced with age [55] and may lead to increased complement activation [56,57].”
BackgroundPerkins, S. J., Okemefuna, A. I., Nan, R., Li, K., & Bonner, A. (2009) · Journal of The Royal Society Interface · doi:10.1098/rsif.2009.0164.focus · Cited by 45 · see citing works
“In the above examples, SEDFIT was used to analyse SC (degradation), FH (oligomerization), C3d and the SCR-6/8 and 16/20 fragments (self-association) prior to their constrained modelling (figure 8).”
ResultInfluentialRelevance of Complement Factor H–Related 1 ( CFHR1 ) Genotypes in Age-Related Macular Degeneration
Martínez‐Barricarte, R., Recalde, S., Fernández‐Robredo, P., Millán, I., Olavarrieta, L., Viñuela, A., Pérez‐Pérez, J., García‐Layana, A., & de Córdoba, S. R. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.11-8709 · Cited by 43 · see citing works
Marson, A., Robinson, D. E., Brookes, P. N., Mulloy, B., Wiles, M., Clark, S. J., Fielder, H. L., Collinson, L. J., Cain, S. A., Kielty, C. M., et al. (2009) · Glycobiology · doi:10.1093/glycob/cwp132 · Cited by 43 · see citing works
“…" -binding domain from complement factor H obtained with the sugar array (Figure 7B) was in agreement with previous studies showing that factor H interacts with heparin and dermatan sulfate (Pangburn et al. 1991; Meri and Pangburn 1994; Saito et al. 2005; Clark et al. 2006; Prosser et al. 2007).”
BackgroundResultSelf-citationNan, R., Farabella, I., Schumacher, F. F., Miller, A., Gor, J., Martin, A. C. R., Jones, D. T., Lengyel, I., & Perkins, S. J. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.03.006 · Cited by 42 · see citing works
Interaction of Complement Factor H and Fibulin3 in Age-Related Macular Degeneration
Wyatt, M. K., Tsai, J.-Y., Mishra, S., Campos, M. M., Jaworski, C. J., Fariss, R. N., Bernstein, S. L., & Wistow, G. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068088 · Cited by 41 · see citing works
“Indeed, differences in binding to C-reactive protein and cell surface components have been described for the 402H/Y variants [47,48].”
BackgroundAlić, L., Papac-Miličević, N., Czamara, D., Rudnick, R. B., Ozsvár-Kozma, M., Hartmann, A., Gurbisz, M., Hoermann, G., Haslinger-Hutter, S., Zipfel, P. F., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1913970117 · Cited by 41 · see citing works
The proteoglycan glycomatrix: A sugar microenvironment essential for complement regulation
Clark, S. J., Bishop, P. N., & Day, A. J. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00412 · Cited by 39 · see citing works
“Our studies have demonstrated that the disease-associated 402H variant has a rather restricted specificity, requiring highly sulfated structures, as opposed to the 402Y form which is able to bind a broader range of GAG sequences (15, 22).”
BackgroundSelf-citationZhang, Q., Long, Q., & Ott, J. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003627 · Cited by 38 · see citing works
“The interaction between glycosaminoglycans (GAGs) and CFH plays an important role in the disease pathology of age-related macular degeneration [43–52].”
BackgroundAredo, B., Li, T., Chen, X., Zhang, K., Wang, C. X.-Z., Gou, D., Zhao, B., He, Y.-G., & Ufret-Vincenty, R. L. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-16089 · Cited by 40 · see citing works
“Several groups have proposed that the relevance of Cfh variants in AMD is due to altered Cfh–GAG interactions,21,83,84 or altered Cfh–Crp interactions,19,80–82 and not related to MDA.”
BackgroundInfluentialde Córdoba, S. R., Harris, C. L., Morgan, B. P., & Llorca, Ó. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.09.002 · Cited by 38 · see citing works
Blaum, B. S., Deakin, J. A., Johansson, C. M., Herbert, A. P., Barlow, P. N., Lyon, M., & Uhrı́n, D. (2010) · Journal of the American Chemical Society · doi:10.1021/ja1000517 · Cited by 39 · see citing works
Self-citationNan, R., Gor, J., & Perkins, S. J. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.11.015 · Cited by 38 · see citing works
Transcriptional control of genes for soluble complement cascade regulatory proteins
Fraczek, L., & Martin, B. K. (2010) · Molecular Immunology · doi:10.1016/j.molimm.2010.08.016 · Cited by 36 · see citing works
Self versus nonself discrimination by the soluble complement regulators factor H and FHL-1
Dopler, A., Guntau, L., Harder, M. J., Palmer, A., Höchsmann, B., Schrezenmeier, H., Simmet, T., Huber-Lang, M., & Schmidt, C. Q. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801545 · Cited by 35 · see citing works
Pappas, C. M., Zouache, M. A., Matthews, S., Faust, C. D., Hageman, J. L., Williams, B. L., Richards, B. T., & Hageman, G. S. (2021) · Human Genomics · doi:10.1186/s40246-021-00359-8 · Cited by 34 · see citing works
Shaughnessy, J., Lewis, L. A., Jarva, H., & Ram, S. (2009) · Infection and Immunity · doi:10.1128/iai.01561-08 · Cited by 35 · see citing works
“The recently solved crystal structure of human fH SCR 6–8402H (His 402 is a polymorphism in SCR 7 that is associated with age-related macular degeneration) in complex with the polyanion sucrose octasulfate (SOS) (38) identified six surface-exposed amino acid residues in SCR 6 that are important for binding to polyanio…”
BackgroundMethodInfluentialMultiple Interactions of Complement Factor H with Its Ligands in Solution: A Progress Report
Perkins, S. J., Nan, R., Okemefuna, A. I., Li, K., Khan, S., & Miller, A. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-5635-4_3 · Cited by 33 · see citing works
“These explanations were supported by the more detailed crystal or NMR structures that followed the homology modellings (Jokiranta et al. 2006; Prosser et al. 2007; Hocking et al. 2008; Wu et al. 2009).”
BackgroundInfluential
- Authors
- Prosser, B. E., Johnson, S., Roversi, P., Herbert, A. P., Blaum, B. S., Tyrrell, J., Jowitt, T. A., Clark, S. J., Tarelli, E., Uhrín, D., Barlow, P. N., Sim, R. B., Day, A. J., & Lea, S. M.
- Affiliations
- University of Oxford (GB)
- 1Sir William Dunn School of Pathology and the
- University of Edinburgh (GB)
- 3Joseph Black Chemistry Building, University of Edinburgh, Edinburgh, EH9 3JJ, Scotland, UK
- Wellcome Centre for Cell-Matrix Research (GB)
- St George's, University of London (GB)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2007-09-24
- Volume
- 204
- Issue
- 10
- Pages
- 2277-2283
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118454
- OpenAlex
- W2138610380
- Cited by
- 184
- References
- 33
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 11 · 2020: 7 · 2019: 4 · 2018: 10 · 2017: 7 · 2016: 8 · 2015: 13 · 2014: 9 · 2013: 11 · 2012: 14
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Figshare (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Wellcome Trust (075415, 078780/Z/05/Z, 078780)
- University of Oxford
- Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- age-related macular degeneration, complement factor H, complement regulation, glycosaminoglycan binding, glycan binding site, multivalent binding, crystal structure, ligand binding, genetic susceptibility
- MeSH terms
- Aging, Binding Sites, Ligands, Models, Molecular, Mutation, Polysaccharides, Sucrose, Surface Properties, Gene Products, gag, Complement Factor H, Protein Structure, Tertiary, Crystallography, X-Ray, Protein Structure, Quaternary
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