2uwn
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Nearly 50 million people worldwide suffer from age-related macular | + | 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 approximately 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. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Barlow, P | + | [[Category: Barlow, P N.]] |
| - | [[Category: Blaum, B | + | [[Category: Blaum, B S.]] |
| - | [[Category: Clark, S | + | [[Category: Clark, S J.]] |
| - | [[Category: Day, A | + | [[Category: Day, A J.]] |
| - | [[Category: Herbert, A | + | [[Category: Herbert, A P.]] |
[[Category: Johnson, S.]] | [[Category: Johnson, S.]] | ||
| - | [[Category: Jowitt, T | + | [[Category: Jowitt, T A.]] |
| - | [[Category: Lea, S | + | [[Category: Lea, S M.]] |
| - | [[Category: Prosser, B | + | [[Category: Prosser, B E.]] |
[[Category: Roversi, P.]] | [[Category: Roversi, P.]] | ||
| - | [[Category: Sim, R | + | [[Category: Sim, R B.]] |
[[Category: Terelli, E.]] | [[Category: Terelli, E.]] | ||
[[Category: Tyrrell, J.]] | [[Category: Tyrrell, J.]] | ||
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[[Category: sushi]] | [[Category: sushi]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:51:06 2008'' |
Revision as of 16:51, 21 February 2008
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CRYSTAL STRUCTURE OF HUMAN COMPLEMENT FACTOR H, SCR DOMAINS 6-8 (H402 RISK VARIANT), IN COMPLEX WITH LIGAND.
Contents |
Overview
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 approximately 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.
Disease
Known diseases associated with this structure: Complement factor H deficiency OMIM:[134370], Factor H and factor H-like 1 OMIM:[134370], Hemolytic-uremic syndrome OMIM:[134370], Macular degeneration, age-related, 4 OMIM:[134370], Membranoproliferative glomerulonephritis with CFH deficiency OMIM:[134370]
About this Structure
2UWN is a Single protein structure of sequence from Homo sapiens with , , and as ligands. Known structural/functional Site: . Full crystallographic information is available from OCA.
Reference
Structural basis for complement factor H linked age-related macular degeneration., Prosser BE, Johnson S, Roversi P, Herbert AP, Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, Uhrin D, Barlow PN, Sim RB, Day AJ, Lea SM, J Exp Med. 2007 Oct 1;204(10):2277-83. Epub 2007 Sep 24. PMID:17893204
Page seeded by OCA on Thu Feb 21 18:51:06 2008
Categories: Homo sapiens | Single protein | Barlow, P N. | Blaum, B S. | Clark, S J. | Day, A J. | Herbert, A P. | Johnson, S. | Jowitt, T A. | Lea, S M. | Prosser, B E. | Roversi, P. | Sim, R B. | Terelli, E. | Tyrrell, J. | Uhrin, D. | ACT | CL | SCR | SO4 | Age-related macular degeneration | Alternative splicing | Complement | Complement alternate pathway | Disease mutation | Factor h | Glycoprotein | Glycosaminoglycan | Immune response | Immune system | Innate immunity | Polymorphism | Sucrose octasulphate | Sushi
