2uwn
From Proteopedia
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==Overview== | ==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. | 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. | ||
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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Complement factor H deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Factor H and factor H-like 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Hemolytic-uremic syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Macular degeneration, age-related, 4 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]], Membranoproliferative glomerulonephritis with CFH deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134370 134370]] | ||
==About this Structure== | ==About this Structure== | ||
| - | 2UWN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SCR:'>SCR</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Site: <scene name='pdbsite=AC1:So4 Binding Site For Chain A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2UWN OCA]. | + | 2UWN is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SCR:'>SCR</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Known structural/functional Site: <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2UWN OCA]. |
==Reference== | ==Reference== | ||
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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 Sun Feb 3 10:47:47 2008'' |
Revision as of 08:47, 3 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 Sun Feb 3 10:47:47 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
