Wiskott–Aldrich syndrome protein

Wiskott-Aldrich syndrome (eczema-thrombocytopenia)

PDB rendering based on 1cee.
Identifiers
Symbols WAS; IMD2; THC; THC1; WASP
External IDs OMIM: 300392 MGI: 105059 HomoloGene: 30970 GeneCards: WAS Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 7454 22376
Ensembl ENSG00000015285 ENSMUSG00000031165
UniProt P42768 Q53WY0
RefSeq (mRNA) NM_000377.2 NM_009515.2
RefSeq (protein) NP_000368.1 NP_033541.1
Location (UCSC) Chr X:
48.53 – 48.55 Mb		 Chr X:
7.66 – 7.67 Mb
PubMed search [1] [2]

The Wiskott–Aldrich Syndrome Protein (WASp) is a 502-amino acid protein that is expressed in cells of the hematopoietic system. In the inactive state, WASp exists in an auto-inhibited conformation with sequences near its C-terminus binding to a region near its N-terminus. Its activation is dependent upon Cdc42 and PIP2 acting to disrupt this interaction causing the WASp protein to 'open'. This exposes a domain near the WASp C-Terminus that binds to and activates the Arp2/3 complex. Activated Arp2/3 nucleates new F-actin. WASp is the founding member of a gene family which also includes the broadly expressed N-WASP (neuronal Wiskott–Aldrich Syndrome protein), and Scar.

Contents

Structure and Function

The Wiskott–Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott–Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5' UTR sequence, has been described, however, its full-length nature is not known.[1]

Genetic diseases associated with WASp

WASp is a product of the WAS gene and mutations in the WAS gene can lead to Wiskott–Aldrich syndrome (an X-linked disease that mainly affects males with symptoms that include thrombocytopenia, eczema, recurrent infections, and small-sized platelets). Other, less inactivating mutations affecting the WAS gene cause X-linked thrombocytopeia, or XLT.

Interactions

Wiskott–Aldrich syndrome protein has been shown to interact with PLCG1,[2][3] Src,[2][3] NCK1,[4][5][6] ITSN2,[7] FGR,[2][3][6] Grb2,[2][8] PSTPIP1,[9] CDC42,[10][11][12][13] TRIP10,[10] WIPF1,[14][15] FYN,[2][6][16] Epidermal growth factor receptor,[8] PIK3R1,[2] ITK[17][18] and CRKL.[19]

See also

References

  1. ^ "Entrez Gene: WAS Wiskott-Aldrich syndrome (eczema-thrombocytopenia)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7454. 
  2. ^ a b c d e f Banin, S; Truong O, Katz D R, Waterfield M D, Brickell P M, Gout I (Aug. 1996). "Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases". Curr. Biol. (ENGLAND) 6 (8): 981–8. doi:10.1016/S0960-9822(02)00642-5. ISSN 0960-9822. PMID 8805332. 
  3. ^ a b c Finan, P M; Soames C J, Wilson L, Nelson D L, Stewart D M, Truong O, Hsuan J J, Kellie S (Oct. 1996). "Identification of regions of the Wiskott-Aldrich syndrome protein responsible for association with selected Src homology 3 domains". J. Biol. Chem. (UNITED STATES) 271 (42): 26291–5. doi:10.1074/jbc.271.42.26291. ISSN 0021-9258. PMID 8824280. 
  4. ^ Krause, M; Sechi A S, Konradt M, Monner D, Gertler F B, Wehland J (Apr. 2000). "Fyn-binding protein (Fyb)/SLP-76-associated protein (SLAP), Ena/vasodilator-stimulated phosphoprotein (VASP) proteins and the Arp2/3 complex link T cell receptor (TCR) signaling to the actin cytoskeleton". J. Cell Biol. (UNITED STATES) 149 (1): 181–94. doi:10.1083/jcb.149.1.181. ISSN 0021-9525. PMC 2175102. PMID 10747096. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2175102. 
  5. ^ Okabe, Seiichi; Fukuda Seiji, Broxmeyer Hal E (Jul. 2002). "Activation of Wiskott-Aldrich syndrome protein and its association with other proteins by stromal cell-derived factor-1alpha is associated with cell migration in a T-lymphocyte line". Exp. Hematol. (Netherlands) 30 (7): 761–6. doi:10.1016/S0301-472X(02)00823-8. ISSN 0301-472X. PMID 12135674. 
  6. ^ a b c Rivero-Lezcano, O M; Marcilla A, Sameshima J H, Robbins K C (Oct. 1995). "Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains". Mol. Cell. Biol. (UNITED STATES) 15 (10): 5725–31. ISSN 0270-7306. PMC 230823. PMID 7565724. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=230823. 
  7. ^ McGavin, M K; Badour K, Hardy L A, Kubiseski T J, Zhang J, Siminovitch K A (Dec. 2001). "The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis". J. Exp. Med. (United States) 194 (12): 1777–87. doi:10.1084/jem.194.12.1777. ISSN 0022-1007. PMC 2193569. PMID 11748279. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2193569. 
  8. ^ a b She, H Y; Rockow S, Tang J, Nishimura R, Skolnik E Y, Chen M, Margolis B, Li W (Sep. 1997). "Wiskott-Aldrich syndrome protein is associated with the adapter protein Grb2 and the epidermal growth factor receptor in living cells". Mol. Biol. Cell (UNITED STATES) 8 (9): 1709–21. ISSN 1059-1524. PMC 305731. PMID 9307968. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=305731. 
  9. ^ Wu, Y; Spencer S D, Lasky L A (Mar. 1998). "Tyrosine phosphorylation regulates the SH3-mediated binding of the Wiskott-Aldrich syndrome protein to PSTPIP, a cytoskeletal-associated protein". J. Biol. Chem. (UNITED STATES) 273 (10): 5765–70. doi:10.1074/jbc.273.10.5765. ISSN 0021-9258. PMID 9488710. 
  10. ^ a b Tian, L; Nelson D L, Stewart D M (Mar. 2000). "Cdc42-interacting protein 4 mediates binding of the Wiskott-Aldrich syndrome protein to microtubules". J. Biol. Chem. (UNITED STATES) 275 (11): 7854–61. doi:10.1074/jbc.275.11.7854. ISSN 0021-9258. PMID 10713100. 
  11. ^ Kim, A S; Kakalis L T, Abdul-Manan N, Liu G A, Rosen M K (Mar. 2000). "Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein". Nature (ENGLAND) 404 (6774): 151–8. doi:10.1038/35004513. ISSN 0028-0836. PMID 10724160. 
  12. ^ Kolluri, R; Tolias K F, Carpenter C L, Rosen F S, Kirchhausen T (May. 1996). "Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 93 (11): 5615–8. doi:10.1073/pnas.93.11.5615. ISSN 0027-8424. PMC 39296. PMID 8643625. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=39296. 
  13. ^ Symons, M; Derry J M, Karlak B, Jiang S, Lemahieu V, Mccormick F, Francke U, Abo A (Mar. 1996). "Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization". Cell (UNITED STATES) 84 (5): 723–34. doi:10.1016/S0092-8674(00)81050-8. ISSN 0092-8674. PMID 8625410. 
  14. ^ Ramesh, N; Antón I M, Hartwig J H, Geha R S (Dec. 1997). "WIP, a protein associated with wiskott-aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 94 (26): 14671–6. doi:10.1073/pnas.94.26.14671. ISSN 0027-8424. PMC 25088. PMID 9405671. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=25088. 
  15. ^ Antón, I M; Lu W, Mayer B J, Ramesh N, Geha R S (Aug. 1998). "The Wiskott-Aldrich syndrome protein-interacting protein (WIP) binds to the adaptor protein Nck". J. Biol. Chem. (UNITED STATES) 273 (33): 20992–5. doi:10.1074/jbc.273.33.20992. ISSN 0021-9258. PMID 9694849. 
  16. ^ Banin, S; Gout I, Brickell P (Aug. 1999). "Interaction between Wiskott-Aldrich Syndrome protein (WASP) and the Fyn protein-tyrosine kinase". Mol. Biol. Rep. (NETHERLANDS) 26 (3): 173–7. doi:10.1023/A:1006954206151. ISSN 0301-4851. PMID 10532312. 
  17. ^ Cory, G O; MacCarthy-Morrogh L, Banin S, Gout I, Brickell P M, Levinsky R J, Kinnon C, Lovering R C (Nov. 1996). "Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways". J. Immunol. (UNITED STATES) 157 (9): 3791–5. ISSN 0022-1767. PMID 8892607. 
  18. ^ Bunnell, S C; Henry P A, Kolluri R, Kirchhausen T, Rickles R J, Berg L J (Oct. 1996). "Identification of Itk/Tsk Src homology 3 domain ligands". J. Biol. Chem. (UNITED STATES) 271 (41): 25646–56. doi:10.1074/jbc.271.41.25646. ISSN 0021-9258. PMID 8810341. 
  19. ^ Oda, A; Ochs H D, Lasky L A, Spencer S, Ozaki K, Fujihara M, Handa M, Ikebuchi K, Ikeda H (May. 2001). "CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk". Blood (United States) 97 (9): 2633–9. doi:10.1182/blood.V97.9.2633. ISSN 0006-4971. PMID 11313252. 

Further reading

External links

Human
A1, A2, B, C1, G1, G2
I (MYO1A, MYO1B, MYO1C, MYO1D, MYO1E, MYO1F, MYO1G, MYO1H) · II (MYH1, MYH2, MYH3, MYH4, MYH6, MYH7, MYH7B, MYH8, MYH9, MYH10, MYH11, MYH13, MYH14, MYH15, MYH16) · III (MYO3A, MYO3B) · V (MYO5A, MYO5B, MYO5C) · VI (MYO6) · VII (MYO7A, MYO7B) · IX (MYO9A, MYO9B) · X (MYO10) · XV (MYO15A) · XVIII (MYO18A, MYO18B) · LC (MYL1, MYL2, MYL3, MYL4, MYL5, MYL6, MYL6B, MYL7, MYL9, MYLIP, MYLK, MYLK2, MYLL1)
Other

Tropomodulin (1, 2, 3, 4) · Troponin (T 1 2 3, C 1 2, I 1 2 3) · Tropomyosin (1, 2, 3, 4)

Actinin (1, 2, 3, 4) · Arp2/3 complex · actin depolymerizing factors (Cofilin (1, 2) · Destrin) · Gelsolin · Profilin (1, 2) · Titin
Other
Type 1/2
(Keratin,
Cytokeratin)
Epithelial keratins
(soft alpha-keratins)

type I/chromosome 17 (10, 12, 13, 14, 15, 16, 17, 19, 20) · chromosome 12 (18) · none (21)

type II/chromosome 12 (1, 2A, 3, 4, 5, 6A, 6B, 7, 8, 9)
Hair keratins
(hard alpha-keratins)
Ungrouped alpha
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Type 3
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Type 5
KIF1A, KIF1B, KIF2A, KIF2C, KIF3B, KIF3C, KIF4A, KIF4B, KIF5A, KIF5B, KIF5C, KIF6, KIF7, KIF9, KIF11, KIF12, KIF13A, KIF13B, KIF14, KIF15, KIF16B, KIF17, KIF18A, KIF18B, KIF19, KIF20A, KIF20B, KIF21A, KIF21B, KIF22, KIF23, KIF24, KIF25, KIF26A, KIF26B, KIF27, KIFC1, KIFC2, KIFC3

axonemal: DNAH1, DNAH2, DNAH3, DNAH5, DNAH6, DNAH7, DNAH8, DNAH9, DNAH10, DNAH11, DNAH12, DNAH13, DNAH14, DNAH17, DNAI1, DNAI2, DNALI1, DNAL1, DNAL4

cytoplasmic: DYNC1H1, DYNC2H1, DYNC1I1, DYNC1I2, DYNC1LI1, DYNC1LI2, DYNC2LI1, DYNLL1, DYNLL2, DYNLRB1, DYNLRB2, DYNLT1, DYNLT3
Other
Tau protein · Dynactin (DCTN1) · Tubulins (TUBA1A, TUBA1B, TUBA1C, TUBA3C, TUBA3D, TUBA3E, TUBA4A, TUBA8) · Stathmin · Tektin (TEKT1, TEKT2, TEKT3, TEKT4, TEKT5) · Dynamin (DNM1, DNM2, DNM3)
Other
Nonhuman
see also cytoskeletal defects
B strc: edmb (perx), skel (ctrs), epit, cili, mito, nucl (chro)