2v8e: Difference between revisions
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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. | ||
==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== | ||
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[[Category: sushi]] | [[Category: sushi]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:42:23 2007'' | ||
