5du3

From Proteopedia

(Difference between revisions)

Current revision

Active form of human C1-inhibitor

Structural highlights

5du3 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IC1_HUMAN Defects in SERPING1 are the cause of hereditary angioedema (HAE) [MIM:106100; also called hereditary angioneurotic edema (HANE). HAE is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In HAE type 1, representing 85% of patients, serum levels of C1 esterase inhibitor are less than 35% of normal. In HAE type 2, the levels are normal or elevated, but the protein is non-functional.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] [:]^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15]

Function

IC1_HUMAN Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.^[16]

Publication Abstract from PubMed

C1-inhibitor is a key inhibitor of the complement and contact activation systems, and mutations in the protein can cause hereditary angioedema. Through an unknown mechanism, polysaccharides can increase C1-inhibitor activity against some of its target proteases. Here we present the crystal structures of the serine protease inhibitor (serpin) domain of active C1-inhibitor by itself and in complex with dextran sulfate. Unlike previously described interactions of serpins with polysaccharides, the structures and isothermal titration calorimetry experiments together reveal that dextran sulfate binds to C1-inhibitor's F1 helix with low affinity and does not invoke an allosteric change. Furthermore, one dextran sulfate molecule can bind multiple C1-inhibitor molecules. We propose that in a C1-inhibitor/protease/polysaccharide ternary complex, negatively charged polysaccharides link C1-inhibitor's positively charged F1 helix to positively charged autolysis loops of proteases. The proposed mechanism elegantly explains previous experiments showing that polysaccharide potentiation is increased against proteases with a greater positive charge in their autolysis loop.

How Dextran Sulfate Affects C1-inhibitor Activity: A Model for Polysaccharide Potentiation.,Dijk M, Holkers J, Voskamp P, Giannetti BM, Waterreus WJ, van Veen HA, Pannu NS Structure. 2016 Dec 6;24(12):2182-2189. doi: 10.1016/j.str.2016.09.013. Epub 2016, Nov 3. PMID:27818099^[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bos IG, Lubbers YT, Roem D, Abrahams JP, Hack CE, Eldering E. The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant. J Biol Chem. 2003 Aug 8;278(32):29463-70. Epub 2003 May 27. PMID:12773530 doi:10.1074/jbc.M302977200
↑ Verpy E, Couture-Tosi E, Eldering E, Lopez-Trascasa M, Spath P, Meo T, Tosi M. Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function. J Clin Invest. 1995 Jan;95(1):350-9. PMID:7814636 doi:http://dx.doi.org/10.1172/JCI117663
↑ Aulak KS, Pemberton PA, Rosen FS, Carrell RW, Lachmann PJ, Harrison RA. Dysfunctional C1-inhibitor(At), isolated from a type II hereditary-angio-oedema plasma, contains a P1 'reactive centre' (Arg444----His) mutation. Biochem J. 1988 Jul 15;253(2):615-8. PMID:3178731
↑ Aulak KS, Cicardi M, Harrison RA. Identification of a new P1 residue mutation (444Arg----Ser) in a dysfunctional C1 inhibitor protein contained in a type II hereditary angioedema plasma. FEBS Lett. 1990 Jun 18;266(1-2):13-6. PMID:2365061
↑ Levy NJ, Ramesh N, Cicardi M, Harrison RA, Davis AE 3rd. Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene. Proc Natl Acad Sci U S A. 1990 Jan;87(1):265-8. PMID:2296585
↑ Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE 3rd. Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6786-90. PMID:2118657
↑ Frangi D, Aulak KS, Cicardi M, Harrison RA, Davis AE 3rd. A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu). FEBS Lett. 1992 Apr 13;301(1):34-6. PMID:1451784
↑ Davis AE 3rd, Aulak K, Parad RB, Stecklein HP, Eldering E, Hack CE, Kramer J, Strunk RC, Bissler J, Rosen FS. C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nat Genet. 1992 Aug;1(5):354-8. PMID:1363816 doi:http://dx.doi.org/10.1038/ng0892-354
↑ Davis AE 3rd, Bissler JJ, Cicardi M. Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema. Behring Inst Mitt. 1993 Dec;(93):313-20. PMID:8172583
↑ Zahedi R, Bissler JJ, Davis AE 3rd, Andreadis C, Wisnieski JJ. Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443-->Val substitution and functional analysis of the recombinant mutant protein. J Clin Invest. 1995 Mar;95(3):1299-305. PMID:7883978 doi:http://dx.doi.org/10.1172/JCI117780
↑ Ocejo-Vinyals JG, Leyva-Cobian F, Fernandez-Luna JL. A mutation unique in serine protease inhibitors (serpins) identified in a family with type II hereditary angioneurotic edema. Mol Med. 1995 Sep;1(6):700-5. PMID:8529136
↑ Verpy E, Biasotto M, Brai M, Misiano G, Meo T, Tosi M. Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema. Am J Hum Genet. 1996 Aug;59(2):308-19. PMID:8755917
↑ Kalmar L, Bors A, Farkas H, Vas S, Fandl B, Varga L, Fust G, Tordai A. Mutation screening of the C1 inhibitor gene among Hungarian patients with hereditary angioedema. Hum Mutat. 2003 Dec;22(6):498. PMID:14635117 doi:10.1002/humu.9202
↑ Kang HR, Yim EY, Oh SY, Chang YS, Kim YK, Cho SH, Min KU, Kim YY. Normal C1 inhibitor mRNA expression level in type I hereditary angioedema patients: newly found C1 inhibitor gene mutations. Allergy. 2006 Feb;61(2):260-4. PMID:16409206 doi:10.1111/j.1398-9995.2006.01010.x
↑ Xu YY, Zhi YX, Yin J, Wang LL, Wen LP, Gu JQ, Guan K, Craig T, Zhang HY. Mutational spectrum and geno-phenotype correlation in Chinese families with hereditary angioedema. Allergy. 2012 Nov;67(11):1430-6. doi: 10.1111/all.12024. Epub 2012 Sep 21. PMID:22994404 doi:10.1111/all.12024
↑ Aulak KS, Davis AE 3rd, Donaldson VH, Harrison RA. Chymotrypsin inhibitory activity of normal C1-inhibitor and a P1 Arg to His mutant: evidence for the presence of overlapping reactive centers. Protein Sci. 1993 May;2(5):727-32. PMID:8495195 doi:http://dx.doi.org/10.1002/pro.5560020504
↑ Dijk M, Holkers J, Voskamp P, Giannetti BM, Waterreus WJ, van Veen HA, Pannu NS. How Dextran Sulfate Affects C1-inhibitor Activity: A Model for Polysaccharide Potentiation. Structure. 2016 Dec 6;24(12):2182-2189. doi: 10.1016/j.str.2016.09.013. Epub 2016, Nov 3. PMID:27818099 doi:http://dx.doi.org/10.1016/j.str.2016.09.013

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5du3"

@@ Line 3: / Line 3: @@
 <StructureSection load='5du3' size='340' side='right'caption='[[5du3]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5du3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DU3 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DU3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5du3]] is a 2 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=5DU3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DU3 FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SERPING1, C1IN, C1NH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 2.1&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5du3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5du3 OCA], [http://pdbe.org/5du3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5du3 RCSB], [http://www.ebi.ac.uk/pdbsum/5du3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5du3 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=5du3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5du3 OCA], [https://pdbe.org/5du3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5du3 RCSB], [https://www.ebi.ac.uk/pdbsum/5du3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5du3 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/IC1_HUMAN IC1_HUMAN]] Defects in SERPING1 are the cause of hereditary angioedema (HAE) [MIM:[http://omim.org/entry/106100 106100]]; also called hereditary angioneurotic edema (HANE). HAE is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In HAE type 1, representing 85% of patients, serum levels of C1 esterase inhibitor are less than 35% of normal. In HAE type 2, the levels are normal or elevated, but the protein is non-functional.<ref>PMID:12773530</ref> <ref>PMID:7814636</ref> <ref>PMID:3178731</ref> <ref>PMID:2365061</ref> <ref>PMID:2296585</ref> <ref>PMID:2118657</ref> [:]<ref>PMID:1451784</ref> <ref>PMID:1363816</ref> <ref>PMID:8172583</ref> <ref>PMID:7883978</ref> <ref>PMID:8529136</ref> <ref>PMID:8755917</ref> <ref>PMID:14635117</ref> <ref>PMID:16409206</ref> <ref>PMID:22994404</ref>
+[https://www.uniprot.org/uniprot/IC1_HUMAN IC1_HUMAN] Defects in SERPING1 are the cause of hereditary angioedema (HAE) [MIM:[https://omim.org/entry/106100 106100]; also called hereditary angioneurotic edema (HANE). HAE is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE due to C1 esterase inhibitor deficiency is comprised of two clinically indistinguishable forms. In HAE type 1, representing 85% of patients, serum levels of C1 esterase inhibitor are less than 35% of normal. In HAE type 2, the levels are normal or elevated, but the protein is non-functional.<ref>PMID:12773530</ref> <ref>PMID:7814636</ref> <ref>PMID:3178731</ref> <ref>PMID:2365061</ref> <ref>PMID:2296585</ref> <ref>PMID:2118657</ref> [:]<ref>PMID:1451784</ref> <ref>PMID:1363816</ref> <ref>PMID:8172583</ref> <ref>PMID:7883978</ref> <ref>PMID:8529136</ref> <ref>PMID:8755917</ref> <ref>PMID:14635117</ref> <ref>PMID:16409206</ref> <ref>PMID:22994404</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/IC1_HUMAN IC1_HUMAN]] Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.<ref>PMID:8495195</ref>
+[https://www.uniprot.org/uniprot/IC1_HUMAN IC1_HUMAN] Activation of the C1 complex is under control of the C1-inhibitor. It forms a proteolytically inactive stoichiometric complex with the C1r or C1s proteases. May play a potentially crucial role in regulating important physiological pathways including complement activation, blood coagulation, fibrinolysis and the generation of kinins. Very efficient inhibitor of FXIIa. Inhibits chymotrypsin and kallikrein.<ref>PMID:8495195</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Dijk, M]]
+[[Category: Dijk M]]
-[[Category: Giannetti, B M]]
+[[Category: Giannetti BM]]
-[[Category: Holkers, J]]
+[[Category: Holkers J]]
-[[Category: Pannu, N S]]
+[[Category: Pannu NS]]
-[[Category: Veen, H A.van]]
+[[Category: Voskamp P]]
-[[Category: Voskamp, P]]
+[[Category: Waterreus WJ]]
-[[Category: Waterreus, W J]]
+[[Category: Van Veen HA]]
-[[Category: Hydrolase inhibitor]]
-[[Category: Serine protease inhibitor]]

5du3

From Proteopedia

Current revision

Active form of human C1-inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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