2k42

From Proteopedia

(Difference between revisions)

Current revision

Solution Structure of the GTPase Binding Domain of WASP in Complex with EspFU, an EHEC Effector

Structural highlights

2k42 is a 2 chain structure with sequence from Escherichia coli O157:H7 and Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

WASP_HUMAN Defects in WAS are the cause of Wiskott-Aldrich syndrome (WAS) [MIM:301000; also known as eczema-thrombocytopenia-immunodeficiency syndrome. WAS is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. Death usually occurs before age 10.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] Defects in WAS are the cause of thrombocytopenia type 1 (THC1) [MIM:313900. Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting.^[12] ^[13] ^[14] ^[15] ^[16] Defects in WAS are a cause of neutropenia severe congenital X-linked (XLN) [MIM:300299. XLN is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia.^[17]

Function

WASP_HUMAN Effector protein for Rho-type GTPases. Regulates actin filament reorganization via its interaction with the Arp2/3 complex. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function. Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria.^[18] ^[19] ^[20]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

During infection, enterohaemorrhagic Escherichia coli (EHEC) takes over the actin cytoskeleton of eukaryotic cells by injecting the EspF(U) protein into the host cytoplasm. EspF(U) controls actin by activating members of the Wiskott-Aldrich syndrome protein (WASP) family. Here we show that EspF(U) binds to the autoinhibitory GTPase binding domain (GBD) in WASP proteins and displaces it from the activity-bearing VCA domain (for verprolin homology, central hydrophobic and acidic regions). This interaction potently activates WASP and neural (N)-WASP in vitro and induces localized actin assembly in cells. In the solution structure of the GBD-EspF(U) complex, EspF(U) forms an amphipathic helix that binds the GBD, mimicking interactions of the VCA domain in autoinhibited WASP. Thus, EspF(U) activates WASP by competing directly for the VCA binding site on the GBD. This mechanism is distinct from that used by the eukaryotic activators Cdc42 and SH2 domains, which globally destabilize the GBD fold to release the VCA. Such diversity of mechanism in WASP proteins is distinct from other multimodular systems, and may result from the intrinsically unstructured nature of the isolated GBD and VCA elements. The structural incompatibility of the GBD complexes with EspF(U) and Cdc42/SH2, plus high-affinity EspF(U) binding, enable EHEC to hijack the eukaryotic cytoskeletal machinery effectively.

Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U).,Cheng HC, Skehan BM, Campellone KG, Leong JM, Rosen MK Nature. 2008 Aug 21;454(7207):1009-13. Epub 2008 Jul 23. PMID:18650809^[21]

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

References

↑ Kwan SP, Hagemann TL, Radtke BE, Blaese RM, Rosen FS. Identification of mutations in the Wiskott-Aldrich syndrome gene and characterization of a polymorphic dinucleotide repeat at DXS6940, adjacent to the disease gene. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4706-10. PMID:7753869
↑ Kolluri R, Shehabeldin A, Peacocke M, Lamhonwah AM, Teichert-Kuliszewska K, Weissman SM, Siminovitch KA. Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus. Hum Mol Genet. 1995 Jul;4(7):1119-26. PMID:8528198
↑ Derry JM, Kerns JA, Weinberg KI, Ochs HD, Volpini V, Estivill X, Walker AP, Francke U. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. 1995 Jul;4(7):1127-35. PMID:8528199
↑ Schindelhauer D, Weiss M, Hellebrand H, Golla A, Hergersberg M, Seger R, Belohradsky BH, Meindl A. Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product. Hum Genet. 1996 Jul;98(1):68-76. PMID:8682510
↑ Remold-O'Donnell E, Cooley J, Shcherbina A, Hagemann TL, Kwan SP, Kenney DM, Rosen FS. Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients. J Immunol. 1997 May 1;158(9):4021-5. PMID:9126958
↑ Ariga T, Yamada M, Sakiyama Y. Mutation analysis of five Japanese families with Wiskott-Aldrich syndrome and determination of the family members' carrier status using three different methods. Pediatr Res. 1997 Apr;41(4 Pt 1):535-40. PMID:9098856 doi:10.1203/00006450-199704000-00013
↑ MacCarthy-Morrogh L, Gaspar HB, Wang YC, Katz F, Thompson L, Layton M, Jones AM, Kinnon C. Absence of expression of the Wiskott-Aldrich syndrome protein in peripheral blood cells of Wiskott-Aldrich syndrome patients. Clin Immunol Immunopathol. 1998 Jul;88(1):22-7. PMID:9683546
↑ Facchetti F, Blanzuoli L, Vermi W, Notarangelo LD, Giliani S, Fiorini M, Fasth A, Stewart DM, Nelson DL. Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott-Aldrich syndrome. J Pathol. 1998 May;185(1):99-107. PMID:9713366 doi:<99::AID-PATH48>3.0.CO;2-L 10.1002/(SICI)1096-9896(199805)185:1<99::AID-PATH48>3.0.CO;2-L
↑ Parolini O, Ressmann G, Haas OA, Pawlowsky J, Gadner H, Knapp W, Holter W. X-linked Wiskott-Aldrich syndrome in a girl. N Engl J Med. 1998 Jan 29;338(5):291-5. PMID:9445409 doi:10.1056/NEJM199801293380504
↑ Lemahieu V, Gastier JM, Francke U. Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Hum Mutat. 1999;14(1):54-66. PMID:10447259 doi:<54::AID-HUMU7>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)14:1<54::AID-HUMU7>3.0.CO;2-E
↑ El-Hakeh J, Rosenzweig S, Oleastro M, Basack N, Berozdnik L, Molina F, Rivas EM, Zelazko M, Danielian S. Wiskott-Aldrich syndrome in Argentina: 17 unique, including nine novel, mutations. Hum Mutat. 2002 Feb;19(2):186-7. PMID:11793485 doi:10.1002/humu.9013
↑ Derry JM, Kerns JA, Weinberg KI, Ochs HD, Volpini V, Estivill X, Walker AP, Francke U. WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. Hum Mol Genet. 1995 Jul;4(7):1127-35. PMID:8528199
↑ Lemahieu V, Gastier JM, Francke U. Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. Hum Mutat. 1999;14(1):54-66. PMID:10447259 doi:<54::AID-HUMU7>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)14:1<54::AID-HUMU7>3.0.CO;2-E
↑ Villa A, Notarangelo L, Macchi P, Mantuano E, Cavagni G, Brugnoni D, Strina D, Patrosso MC, Ramenghi U, Sacco MG, et al.. X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet. 1995 Apr;9(4):414-7. PMID:7795648 doi:http://dx.doi.org/10.1038/ng0495-414
↑ Ho LL, Ayling J, Prosser I, Kronenberg H, Iland H, Joshua D. Missense C168T in the Wiskott--Aldrich Syndrome protein gene is a common mutation in X-linked thrombocytopenia. Br J Haematol. 2001 Jan;112(1):76-80. PMID:11167787
↑ Notarangelo LD, Mazza C, Giliani S, D'Aria C, Gandellini F, Ravelli C, Locatelli MG, Nelson DL, Ochs HD, Notarangelo LD. Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia. Blood. 2002 Mar 15;99(6):2268-9. PMID:11877312
↑ Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, Van Den Oord JJ, Verhoef GE, Boogaerts MA, Fryns JP, You D, Rosen MK, Vandenberghe P. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 2001 Mar;27(3):313-7. PMID:11242115 doi:10.1038/85886
↑ Cory GO, Garg R, Cramer R, Ridley AJ. Phosphorylation of tyrosine 291 enhances the ability of WASp to stimulate actin polymerization and filopodium formation. Wiskott-Aldrich Syndrome protein. J Biol Chem. 2002 Nov 22;277(47):45115-21. Epub 2002 Sep 15. PMID:12235133 doi:10.1074/jbc.M203346200
↑ Chereau D, Kerff F, Graceffa P, Grabarek Z, Langsetmo K, Dominguez R. Actin-bound structures of Wiskott-Aldrich syndrome protein (WASP)-homology domain 2 and the implications for filament assembly. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16644-9. Epub 2005 Nov 7. PMID:16275905
↑ Cheng HC, Skehan BM, Campellone KG, Leong JM, Rosen MK. Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U). Nature. 2008 Aug 21;454(7207):1009-13. Epub 2008 Jul 23. PMID:18650809 doi:10.1038/nature07160
↑ Cheng HC, Skehan BM, Campellone KG, Leong JM, Rosen MK. Structural mechanism of WASP activation by the enterohaemorrhagic E. coli effector EspF(U). Nature. 2008 Aug 21;454(7207):1009-13. Epub 2008 Jul 23. PMID:18650809 doi:10.1038/nature07160

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2k42"

@@ Line 1: / Line 1: @@
 ==Solution Structure of the GTPase Binding Domain of WASP in Complex with EspFU, an EHEC Effector==
-<StructureSection load='2k42' size='340' side='right' caption='[[2k42]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='2k42' size='340' side='right'caption='[[2k42]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2k42]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Escherichia_coli_o157:h7 Escherichia coli o157:h7] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K42 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2K42 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2k42]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_O157:H7 Escherichia coli O157:H7] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K42 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K42 FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">WAS, IMD2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), tccP, ECs2715 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83334 Escherichia coli O157:H7])</td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=2k42 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k42 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2k42 RCSB], [http://www.ebi.ac.uk/pdbsum/2k42 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=2k42 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k42 OCA], [https://pdbe.org/2k42 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k42 RCSB], [https://www.ebi.ac.uk/pdbsum/2k42 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k42 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/WASP_HUMAN WASP_HUMAN]] Defects in WAS are the cause of Wiskott-Aldrich syndrome (WAS) [MIM:[http://omim.org/entry/301000 301000]]; also known as eczema-thrombocytopenia-immunodeficiency syndrome. WAS is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. Death usually occurs before age 10.<ref>PMID:7753869</ref> <ref>PMID:8528198</ref> <ref>PMID:8528199</ref> <ref>PMID:8682510</ref> <ref>PMID:9126958</ref> <ref>PMID:9098856</ref> <ref>PMID:9683546</ref> <ref>PMID:9713366</ref> <ref>PMID:9445409</ref> <ref>PMID:10447259</ref> <ref>PMID:11793485</ref>   Defects in WAS are the cause of thrombocytopenia type 1 (THC1) [MIM:[http://omim.org/entry/313900 313900]]. Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting.<ref>PMID:8528199</ref> <ref>PMID:10447259</ref> <ref>PMID:7795648</ref> <ref>PMID:11167787</ref> <ref>PMID:11877312</ref>   Defects in WAS are a cause of neutropenia severe congenital X-linked (XLN) [MIM:[http://omim.org/entry/300299 300299]]. XLN is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia.<ref>PMID:11242115</ref>
+[https://www.uniprot.org/uniprot/WASP_HUMAN WASP_HUMAN] Defects in WAS are the cause of Wiskott-Aldrich syndrome (WAS) [MIM:[https://omim.org/entry/301000 301000]; also known as eczema-thrombocytopenia-immunodeficiency syndrome. WAS is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. Death usually occurs before age 10.<ref>PMID:7753869</ref> <ref>PMID:8528198</ref> <ref>PMID:8528199</ref> <ref>PMID:8682510</ref> <ref>PMID:9126958</ref> <ref>PMID:9098856</ref> <ref>PMID:9683546</ref> <ref>PMID:9713366</ref> <ref>PMID:9445409</ref> <ref>PMID:10447259</ref> <ref>PMID:11793485</ref>   Defects in WAS are the cause of thrombocytopenia type 1 (THC1) [MIM:[https://omim.org/entry/313900 313900]. Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting.<ref>PMID:8528199</ref> <ref>PMID:10447259</ref> <ref>PMID:7795648</ref> <ref>PMID:11167787</ref> <ref>PMID:11877312</ref>   Defects in WAS are a cause of neutropenia severe congenital X-linked (XLN) [MIM:[https://omim.org/entry/300299 300299]. XLN is an immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia.<ref>PMID:11242115</ref>
 == Function ==
-[[http://www.uniprot.org/uniprot/WASP_HUMAN WASP_HUMAN]] Effector protein for Rho-type GTPases. Regulates actin filament reorganization via its interaction with the Arp2/3 complex. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function. Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria.<ref>PMID:12235133</ref> <ref>PMID:16275905</ref> <ref>PMID:18650809</ref>  [[http://www.uniprot.org/uniprot/Q8X2D5_ECO57 Q8X2D5_ECO57]] Required for efficient pedestal formation in host epithelial cells during infection. Acts as an intermediate between Tir (via host BAIAP2) and host WASL/N-WASP. Directly binds and activates WASL/N-WASP, which stimulates actin polymerization and leads to the formation of actin pedestals at the sites of bacterial adhesion (By similarity).
+[https://www.uniprot.org/uniprot/WASP_HUMAN WASP_HUMAN] Effector protein for Rho-type GTPases. Regulates actin filament reorganization via its interaction with the Arp2/3 complex. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function. Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria.<ref>PMID:12235133</ref> <ref>PMID:16275905</ref> <ref>PMID:18650809</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k4/2k42_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k4/2k42_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2k42 ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 28: / Line 29: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2k42" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Wiskott-Aldrich syndrome protein 3D structures|Wiskott-Aldrich syndrome protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Escherichia coli o157:h7]]
+[[Category: Escherichia coli O157:H7]]
 [[Category: Homo sapiens]]
-[[Category: Campellone, K G]]
+[[Category: Large Structures]]
-[[Category: Cheng, H C]]
+[[Category: Campellone KG]]
-[[Category: Leong, J M]]
+[[Category: Cheng H-C]]
-[[Category: Rosen, M K]]
+[[Category: Leong JM]]
-[[Category: Skehan, B M]]
+[[Category: Rosen MK]]
-[[Category: Autoinhibition]]
+[[Category: Skehan BM]]
-[[Category: Cytoskeleton]]
-[[Category: Disease mutation]]
-[[Category: Espfu]]
-[[Category: Gbd]]
-[[Category: Phosphoprotein]]
-[[Category: Signaling protein]]
-[[Category: Wasp]]

2k42

From Proteopedia

Current revision

Solution Structure of the GTPase Binding Domain of WASP in Complex with EspFU, an EHEC Effector

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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