Wiskott–Aldrich syndrome protein
PDB rendering based on 1cee.
|Symbols||; IMD2; SCNX; THC; THC1; WASP|
|RNA expression pattern|
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 CDC 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 organizing complex, Arp2/3.
The WASp family includes both WASp, which is expressed exclusively in hematopoietic cells, and neuronal WASp (N-WASp), which is expressed ubiquitously. In its inactive state, N-WASp is autoinhibited and bound to Arp2/3. Cooperative binding of CDC42 and PIP2 relieve the autoinhibition of N-WASp, causing Arp2/3 to carry out actin polymerization.
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.
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.
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). Other, less inactivating mutations affecting the WASp cause X-linked thrombocytopeia, or XLT. 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.
Wiskott–Aldrich syndrome protein has been shown to interact with:
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- "Entrez Gene: WAS Wiskott-Aldrich syndrome (eczema-thrombocytopenia)".
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- 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)