Wiskott–Aldrich syndrome protein

Wiskott-Aldrich syndrome
250px PDB rendering based on 1cee.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1CEE, 1EJ5, 1T84, 2A3Z, 2K42, 2OT0
Identifiers
Symbols	WAS ; IMD2; SCNX; THC; THC1; WASP; WASPA
External IDs	OMIM: 300392 MGI: 105059 HomoloGene: 30970 GeneCards: WAS Gene
Gene ontology Molecular function • actin binding • protein binding • SH3 domain binding • protein kinase binding • GTPase regulator activity • identical protein binding • phospholipase binding Cellular component • cytosol • cell-cell junction • vesicle membrane • actin cytoskeleton • extracellular exosome Biological process • regulation of T cell antigen processing and presentation • protein complex assembly • defense response • immune response • small GTPase mediated signal transduction • blood coagulation • actin polymerization or depolymerization • epidermis development • endosomal transport • actin filament polymerization • actin filament-based movement • Fc-gamma receptor signaling pathway involved in phagocytosis • T cell activation • innate immune response • regulation of catalytic activity • T cell receptor signaling pathway • negative regulation of cell motility • positive regulation of Arp2/3 complex-mediated actin nucleation Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE WAS 38964 r at tn.png
File:PBB GE WAS 205400 at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7454	22376
Ensembl	ENSG00000015285	ENSMUSG00000031165
UniProt	P42768	P70315
RefSeq (mRNA)	NM_000377	NM_009515
RefSeq (protein)	NP_000368	NP_033541
Location (UCSC)	Chr X: 48.68 – 48.69 Mb	Chr X: 8.08 – 8.09 Mb
PubMed search	[1]	[2]

The Wiskott–Aldrich Syndrome protein (WASp) is a 502-amino acid protein expressed in cells of the hematopoietic system. In the inactive state, WASp exists in an autoinhibited 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.

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 they are regulated by a number of different stimuli, and interact with multiple proteins. These proteins, directly or indirectly, associate with the small GTPase CDC42, known to regulate formation of actin filaments, and the cytoskeletal organising complex, Arp2/3.

The WASp family proteins includes WASp, N-WASp, SCAR/WAVE, WHAMM and WASH the five of them share a C- terminal VCA (verprolin,cofilin, acidic) domain where they interact with actin nucleating complex (ARP2/3) and they differ in their terminal domains. WASp and N-WASP are analogs, they contain an N-terminal EVH1 domain, a C-terminal VCA domain and central B and GBD (GTP binding domain) domains. WASp, is expressed exclusively in hematopoietic cells and neuronal WASp (N-WASp), is ubiquitously expressed. N-WASp contains an output region and a control region that are essential for its regulation. The output region is called the VCA domain. It is located towards the C-terminal end of the protein and contains three motifs: the verprolin homology motif (V) binds actin monomers and delivers them to Arp2/3; the cofilin homology motif (C) binds cofilin; and the acidic motif (A) binds Arp2/3. In isolation, the VCA region is constitutively active. However, in full-length N-WASp the control region suppresses VCA domain activity. The control region is located at N-terminal end of N-WASPp. The control region contains a CDC42-binding domain (GBP) and a PIP2-binding domain (B), both of which are critical for proper regulation of N-WASp. Cooperative binding of CDC42 and PIP2 relieve the autoinhibition of N-WASp, causing Arp2/3 to carry out actin polymerization. WASp interacting protein (WIP) interacts with WASp N-terminal domain (WH1) preventing it from degradation and stabilising its auto-inhibitory conformation.

In the absence of CDC42 and PIP2, N-WASp is in an inactive, locked conformation. Cooperative binding of both CDC42 and PIP2 relieve the autoinhibition. The cooperative binding of CDC42 and PIP2 is thermodynamically favored; binding of one enhances binding of the other. CDC42 and PIP2 localize the N-WASp-Arp2/3 complex to the plasma membrane. This localization ensures the actin polymers will be able to push through the plasma membrane and form filopodium required for cell motility.

WASp is required for various functions in myeloid and lymphoid immune cells, Many of these, such as phagocytosis and podosome formation, related to its role in regulating the polymerization of actin filaments. Other functions of WASP depend on its activity as a scaffold protein for assembly of effective signalling complexes downstream of antigen receptor or integrin engagement. Particularly in NK cells it participates in the synapse formation and polarization of perforin to the immune synapse for NK cell cytotoxicity. When WASp is absent or mutated T cells and B cells formation of immune synapse and TCR/BCR downstream signaling is also affected.

Clinical significance

Wiskott–Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WASp gene. The WASp 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, but its full-length nature is not known.

WASp is a product of the WASp, and mutations in the WASp 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) in these patients the protein is usually significantly reduced or absent. Other, less inactivating mutations affecting the WASp cause X-linked thrombocytopeia, or XLT, where there is usually detectable protein levels by flow cytometry. The majority of the mutations causing classic WAS are located in the WH1 domain of the protein and these mutations affect binding with the WASp Interacting Protein. Mutations located in the GBD domain disrupt autoinhibition and lead to an unfolded protein that is constituvely active. Unlike WAS and XLT, WASp in this case is present and active. Activated WASP leads to nuclear localization of actin filaments and this can lead to premature apoptosis, aneuploidy and failure to undergo cytokinesis causing myelodisplasia and X- linked neutropenia.

Interactions

Wiskott–Aldrich syndrome protein has been shown to interact with:

• CDC42,
• CRKL,
• EGFR,
• FGR,
• FYN,
• Grb2,
• ITK
• ITSN2,
• NCK1,
• PIK3R1,
• PLCG1,
• PSTPIP1,
• Src,
• TRIP10, and
• WIPF1.

See also

• Wiskott–Aldrich syndrome-like
• cortactin

External links

• MBInfo - WASP and other Nucleation Promotion Factors
• GeneReviews/NIH/NCBI/UW entry on WAS-Related Disorders including Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN)
• Online 'Mendelian Inheritance in Man' (OMIM) 300392
• Online 'Mendelian Inheritance in Man' (OMIM) 313900
• Wiskott-Aldrich Syndrome Protein at the US National Library of Medicine Medical Subject Headings (MeSH)