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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.〔Thrasher A. Nature immunology Reviews. March 2010〕 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. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Wiskott–Aldrich syndrome protein」の詳細全文を読む スポンサード リンク
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