[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] [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).
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
↑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
↑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
↑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:https://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
