|
|
| Line 3: |
Line 3: |
| | <StructureSection load='6rur' size='340' side='right'caption='[[6rur]], [[Resolution|resolution]] 6.00Å' scene=''> | | <StructureSection load='6rur' size='340' side='right'caption='[[6rur]], [[Resolution|resolution]] 6.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6rur]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5m6w 5m6w]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RUR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RUR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6rur]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=5m6w 5m6w]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RUR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RUR 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=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 6Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alternative-complement-pathway_C3/C5_convertase Alternative-complement-pathway C3/C5 convertase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.47 3.4.21.47] </span></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=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=6rur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rur OCA], [http://pdbe.org/6rur PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rur RCSB], [http://www.ebi.ac.uk/pdbsum/6rur PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rur ProSAT]</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=6rur FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rur OCA], [https://pdbe.org/6rur PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rur RCSB], [https://www.ebi.ac.uk/pdbsum/6rur PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rur ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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> [[http://www.uniprot.org/uniprot/PROP_HUMAN PROP_HUMAN]] Defects in CFP are the cause of properdin deficiency (PFD) [MIM:[http://omim.org/entry/312060 312060]]. PFD results in higher susceptibility to bacterial infections; especially to meningococcal infections. Three phenotypes have been reported: complete deficiency (type I), incomplete deficiency (type II), and dysfunction of properdin (type III).<ref>PMID:8871668</ref> <ref>PMID:9710744</ref> <ref>PMID:10909851</ref> [[http://www.uniprot.org/uniprot/CFAB_HUMAN CFAB_HUMAN]] Defects in CFB are a cause of susceptibility to hemolytic uremic syndrome atypical type 4 (AHUS4) [MIM:[http://omim.org/entry/612924 612924]]. 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:17182750</ref> <ref>PMID:20513133</ref> | + | [https://www.uniprot.org/uniprot/PROP_HUMAN PROP_HUMAN] Defects in CFP are the cause of properdin deficiency (PFD) [MIM:[https://omim.org/entry/312060 312060]. PFD results in higher susceptibility to bacterial infections; especially to meningococcal infections. Three phenotypes have been reported: complete deficiency (type I), incomplete deficiency (type II), and dysfunction of properdin (type III).<ref>PMID:8871668</ref> <ref>PMID:9710744</ref> <ref>PMID:10909851</ref> |
| | == Function == | | == Function == |
| - | [[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> [[http://www.uniprot.org/uniprot/PROP_HUMAN PROP_HUMAN]] A positive regulator of the alternate pathway of complement. It binds to and stabilizes the C3- and C5-convertase enzyme complexes. [[http://www.uniprot.org/uniprot/CFAB_HUMAN CFAB_HUMAN]] Factor B which is part of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. It has also been implicated in proliferation and differentiation of preactivated B-lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes. Ba inhibits the proliferation of preactivated B-lymphocytes. | + | [https://www.uniprot.org/uniprot/PROP_HUMAN PROP_HUMAN] A positive regulator of the alternate pathway of complement. It binds to and stabilizes the C3- and C5-convertase enzyme complexes. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| - | The 54 kDa protein properdin, also known as factor P (FP), plays a major role in the complement system through the stabilization of the alternative pathway convertases. FP circulates in the blood as cyclic dimers, trimers and tetramers, and this heterogeneity challenges detailed structural insight into the mechanism of convertase stabilization by FP. Here, the generation of an intact FP monomer and a variant monomer with the third thrombospondin repeat liberated is described. Both FP monomers were excised from recombinant full-length FP containing internal cleavage sites for TEV protease. These FP monomers could be crystallized, and complete data sets extending to 2.8 A resolution for the intact FP monomer and to 3.5 A resolution for the truncated variant were collected. The principle of specific monomer excision and domain removal by the insertion of a protease cleavage site may be broadly applicable to structural studies of oligomeric, flexible and modular proteins.
| + | Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg(2+) in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition. |
| | | | |
| - | Crystallization and X-ray analysis of monodisperse human properdin.,Pedersen DV, Revel M, Gadeberg TAF, Andersen GR Acta Crystallogr F Struct Biol Commun. 2019 Feb 1;75(Pt 2):0. doi:, 10.1107/S2053230X18018150. Epub 2019 Jan 23. PMID:30713161<ref>PMID:30713161</ref>
| + | Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System.,Pedersen DV, Gadeberg TAF, Thomas C, Wang Y, Joram N, Jensen RK, Mazarakis SMM, Revel M, El Sissy C, Petersen SV, Lindorff-Larsen K, Thiel S, Laursen NS, Fremeaux-Bacchi V, Andersen GR Front Immunol. 2019 Aug 22;10:2007. doi: 10.3389/fimmu.2019.02007. eCollection , 2019. PMID:31507604<ref>PMID:31507604</ref> |
| | | | |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | <div class="pdbe-citations 6rur" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6rur" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Complement C3 3D structures|Complement C3 3D structures]] |
| | + | *[[Complement factor 3D structures|Complement factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Alternative-complement-pathway C3/C5 convertase]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Andersen, G R]] | + | [[Category: Staphylococcus aureus]] |
| - | [[Category: Gadeberg, T A.F]] | + | [[Category: Andersen GR]] |
| - | [[Category: Pedersen, D V]] | + | [[Category: Gadeberg TAF]] |
| - | [[Category: Complement]] | + | [[Category: Pedersen DV]] |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Innate immunity]]
| + | |
| - | [[Category: Protease]]
| + | |
| Structural highlights
6rur is a 12 chain structure with sequence from Homo sapiens and Staphylococcus aureus. This structure supersedes the now removed PDB entry 5m6w. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 6Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
PROP_HUMAN Defects in CFP are the cause of properdin deficiency (PFD) [MIM:312060. PFD results in higher susceptibility to bacterial infections; especially to meningococcal infections. Three phenotypes have been reported: complete deficiency (type I), incomplete deficiency (type II), and dysfunction of properdin (type III).[1] [2] [3]
Function
PROP_HUMAN A positive regulator of the alternate pathway of complement. It binds to and stabilizes the C3- and C5-convertase enzyme complexes.
Publication Abstract from PubMed
Properdin (FP) is a positive regulator of the immune system stimulating the activity of the proteolytically active C3 convertase C3bBb in the alternative pathway of the complement system. Here we present two crystal structures of FP and two structures of convertase bound FP. A structural core formed by three thrombospondin repeats (TSRs) and a TB domain harbors the convertase binding site in FP that mainly interacts with C3b. Stabilization of the interaction between the C3b C-terminus and the MIDAS bound Mg(2+) in the Bb protease by FP TSR5 is proposed to underlie FP convertase stabilization. Intermolecular contacts between FP and the convertase subunits suggested by the structure were confirmed by binding experiments. FP is shown to inhibit C3b degradation by FI due to a direct competition for a common binding site on C3b. FP oligomers are held together by two sets of intermolecular contacts, where the first is formed by the TB domain from one FP molecule and TSR4 from another. The second and largest interface is formed by TSR1 and TSR6 from the same two FP molecules. Flexibility at four hinges between thrombospondin repeats is suggested to enable the oligomeric, polydisperse, and extended architecture of FP. Our structures rationalize the effects of mutations associated with FP deficiencies and provide a structural basis for the analysis of FP function in convertases and its possible role in pattern recognition.
Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System.,Pedersen DV, Gadeberg TAF, Thomas C, Wang Y, Joram N, Jensen RK, Mazarakis SMM, Revel M, El Sissy C, Petersen SV, Lindorff-Larsen K, Thiel S, Laursen NS, Fremeaux-Bacchi V, Andersen GR Front Immunol. 2019 Aug 22;10:2007. doi: 10.3389/fimmu.2019.02007. eCollection , 2019. PMID:31507604[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Fredrikson GN, Westberg J, Kuijper EJ, Tijssen CC, Sjoholm AG, Uhlen M, Truedsson L. Molecular characterization of properdin deficiency type III: dysfunction produced by a single point mutation in exon 9 of the structural gene causing a tyrosine to aspartic acid interchange. J Immunol. 1996 Oct 15;157(8):3666-71. PMID:8871668
- ↑ Fredrikson GN, Gullstrand B, Westberg J, Sjoholm AG, Uhlen M, Truedsson L. Expression of properdin in complete and incomplete deficiency: normal in vitro synthesis by monocytes in two cases with properdin deficiency type II due to distinct mutations. J Clin Immunol. 1998 Jul;18(4):272-82. PMID:9710744
- ↑ van den Bogaard R, Fijen CA, Schipper MG, de Galan L, Kuijper EJ, Mannens MM. Molecular characterisation of 10 Dutch properdin type I deficient families: mutation analysis and X-inactivation studies. Eur J Hum Genet. 2000 Jul;8(7):513-8. PMID:10909851 doi:10.1038/sj.ejhg.5200496
- ↑ Pedersen DV, Gadeberg TAF, Thomas C, Wang Y, Joram N, Jensen RK, Mazarakis SMM, Revel M, El Sissy C, Petersen SV, Lindorff-Larsen K, Thiel S, Laursen NS, Fremeaux-Bacchi V, Andersen GR. Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System. Front Immunol. 2019 Aug 22;10:2007. PMID:31507604 doi:10.3389/fimmu.2019.02007
|
