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==Ternary host recognition complex of complement factor H, C3d, and sialic acid==
==Ternary host recognition complex of complement factor H, C3d, and sialic acid==
<StructureSection load='4ont' size='340' side='right' caption='[[4ont]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
<StructureSection load='4ont' size='340' side='right'caption='[[4ont]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ont]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ONT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ONT FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ont]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ONT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ONT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BGC:BETA-D-GLUCOSE'>BGC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BGC:BETA-D-GLUCOSE'>BGC</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SIA:O-SIALIC+ACID'>SIA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ont FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ont OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ont RCSB], [http://www.ebi.ac.uk/pdbsum/4ont PDBsum]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ont FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ont OCA], [https://pdbe.org/4ont PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ont RCSB], [https://www.ebi.ac.uk/pdbsum/4ont PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ont ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/CFAH_HUMAN CFAH_HUMAN]] Genetic variations in CFH are associated with basal laminar drusen (BLD) [MIM:[http://omim.org/entry/126700 126700]]; also known as drusen of Bruch membrane or cuticular drusen or grouped early adult-onset drusen. Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch membrane. Basal laminar drusen refers to an early adult-onset drusen phenotype that shows a pattern of uniform small, slightly raised yellow subretinal nodules randomly scattered in the macula. In later stages, these drusen often become more numerous, with clustered groups of drusen scattered throughout the retina. In time these small basal laminar drusen may expand and ultimately lead to a serous pigment epithelial detachment of the macula that may result in vision loss.  Defects in CFH are the cause of complement factor H deficiency (CFHD) [MIM:[http://omim.org/entry/609814 609814]]. A disorder that can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3, and a decrease in other terminal complement components, indicating activation of the alternative complement pathway. It is associated with a number of renal diseases with variable clinical presentation and progression, including membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome.<ref>PMID:9312129</ref> <ref>PMID:10803850</ref> <ref>PMID:11170895</ref> <ref>PMID:11170896</ref> <ref>PMID:11158219</ref> <ref>PMID:12020532</ref> <ref>PMID:14978182</ref> <ref>PMID:16612335</ref>  Defects in CFH are a cause of susceptibility to hemolytic uremic syndrome atypical type 1 (AHUS1) [MIM:[http://omim.org/entry/235400 235400]]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:14978182</ref> <ref>PMID:9551389</ref> <ref>PMID:10577907</ref> <ref>PMID:10762557</ref> <ref>PMID:11851332</ref> <ref>PMID:14583443</ref> <ref>PMID:12960213</ref> <ref>PMID:20513133</ref>  Genetic variation in CFH is associated with age-related macular degeneration type 4 (ARMD4) [MIM:[http://omim.org/entry/610698 610698]]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid (known as drusen) that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:22019782</ref>  [[http://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN]] Defects in C3 are the cause of complement component 3 deficiency (C3D) [MIM:[http://omim.org/entry/613779 613779]]. A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis.<ref>PMID:19913840</ref> <ref>PMID:9596584</ref> <ref>PMID:11387479</ref> <ref>PMID:15713468</ref> <ref>PMID:7961791</ref> [:]  Genetic variation in C3 is associated with susceptibility to age-related macular degeneration type 9 (ARMD9) [MIM:[http://omim.org/entry/611378 611378]]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:19913840</ref> <ref>PMID:17634448</ref>  Defects in C3 are a cause of susceptibility to hemolytic uremic syndrome atypical type 5 (AHUS5) [MIM:[http://omim.org/entry/612925 612925]]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:19913840</ref> <ref>PMID:18796626</ref> <ref>PMID:20513133</ref>  Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.<ref>PMID:19913840</ref>
[https://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN] Defects in C3 are the cause of complement component 3 deficiency (C3D) [MIM:[https://omim.org/entry/613779 613779]. A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis.<ref>PMID:19913840</ref> <ref>PMID:9596584</ref> <ref>PMID:11387479</ref> <ref>PMID:15713468</ref> <ref>PMID:7961791</ref> [:]  Genetic variation in C3 is associated with susceptibility to age-related macular degeneration type 9 (ARMD9) [MIM:[https://omim.org/entry/611378 611378]. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.<ref>PMID:19913840</ref> <ref>PMID:17634448</ref>  Defects in C3 are a cause of susceptibility to hemolytic uremic syndrome atypical type 5 (AHUS5) [MIM:[https://omim.org/entry/612925 612925]. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.<ref>PMID:19913840</ref> <ref>PMID:18796626</ref> <ref>PMID:20513133</ref>  Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.<ref>PMID:19913840</ref>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/CFAH_HUMAN CFAH_HUMAN]] Factor H functions as a cofactor in the inactivation of C3b by factor I and also increases the rate of dissociation of the C3bBb complex (C3 convertase) and the (C3b)NBB complex (C5 convertase) in the alternative complement pathway. [[http://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN]] C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>  Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>  Acylation stimulating protein (ASP): adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for GPR77. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of GPR77.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>
[https://www.uniprot.org/uniprot/CO3_HUMAN CO3_HUMAN] C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>  Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>  Acylation stimulating protein (ASP): adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for GPR77. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of GPR77.<ref>PMID:8376604</ref> <ref>PMID:2909530</ref> <ref>PMID:9059512</ref> <ref>PMID:9555951</ref> <ref>PMID:10432298</ref> <ref>PMID:15833747</ref> <ref>PMID:16333141</ref> <ref>PMID:19615750</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The serum protein complement factor H (FH) ensures downregulation of the complement alternative pathway, a branch of innate immunity, upon interaction with specific glycans on host cell surfaces. Using ligand-based NMR, we screened a comprehensive set of sialylated glycans for binding to FH and solved the crystal structure of a ternary complex formed by the two C-terminal domains of FH, a sialylated trisaccharide and the complement C3b thioester-containing domain. Key residues in the sialic acid binding site are conserved from mice to men, and residues linked to atypical hemolytic uremic syndrome cluster within this binding site, suggesting a possible role for sialic acid as a host marker also in other mammals and a critical role in human renal complement homeostasis. Unexpectedly, the FH sialic acid binding site is structurally homologous to the binding sites of two evolutionarily unrelated proteins. The crystal structure also advances our understanding of bacterial immune evasion strategies.
 
Structural basis for sialic acid-mediated self-recognition by complement factor H.,Blaum BS, Hannan JP, Herbert AP, Kavanagh D, Uhrin D, Stehle T Nat Chem Biol. 2014 Nov 24. doi: 10.1038/nchembio.1696. PMID:25402769<ref>PMID:25402769</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ont" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Complement factor 3D structures|Complement factor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Blaum, B S]]
[[Category: Homo sapiens]]
[[Category: Stehle, T S]]
[[Category: Large Structures]]
[[Category: Ccp]]
[[Category: Blaum BS]]
[[Category: Complement control protein]]
[[Category: Stehle TS]]
[[Category: Complement regulation]]
[[Category: Host cell surface]]
[[Category: Host glycan]]
[[Category: Immune system]]
[[Category: Scr]]
[[Category: Short consensus repeat]]
[[Category: Sialic acid]]
[[Category: Sushi domain]]

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