View source for Wiskott–Aldrich syndrome protein

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{{Short description|Mammalian protein found in humans}}
{{Use dmy dates|date=December 2020}}
{{Infobox gene}}
The '''Wiskott–Aldrich syndrome protein''' ('''WASp''') is a 502-[[amino acid]] protein expressed in cells of the [[hematopoietic]] system that in humans is encoded by the ''WAS'' [[gene]].  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 [[nucleate]]s new F-[[actin]].

{{anchor|Family}}WASp is the founding member of a gene family which also includes the broadly expressed [[N-WASP]] (neuronal Wiskott–Aldrich syndrome protein), [[Scar (protein)|SCAR]]/[[WAVE1]], [[WASHC1|WASH]], [[WHAMM]], and [[JMY (gene)|JMY]].<ref>{{cite journal | vauthors = Pollitt AY, Insall RH | title = WASP and SCAR/WAVE proteins: the drivers of actin assembly | journal = Journal of Cell Science | volume = 122 | issue = Pt 15 | pages = 2575–8 | date = August 2009 | pmid = 19625501 | pmc = 2954249 | doi = 10.1242/jcs.023879 }}</ref><ref>{{cite journal | vauthors = Burianek LE, Soderling SH | title = Under lock and key: spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes | journal = Seminars in Cell & Developmental Biology | volume = 24 | issue = 4 | pages = 258–66 | date = April 2013 | pmid = 23291261 | pmc = 3656410 | doi = 10.1016/j.semcdb.2012.12.005 }}</ref> WAML (WASP and MIM like), WAWH (WASP without WH1 domain), and WHIMP (WAVE Homology in Membrane Protrusions) have more recently been discovered.<ref>{{cite journal | vauthors = Oda A, Eto K | title = WASPs and WAVEs: from molecular function to physiology in hematopoietic cells | journal = Seminars in Cell & Developmental Biology | volume = 24 | issue = 4 | pages = 308–13 | date = April 2013 | pmid = 23499790 | doi = 10.1016/j.semcdb.2013.03.002 | series = WASP/WAVE proteins: expanding members and functions & The role of ploidy variation on cellular adaptation }}</ref><ref>{{Cite journal|last1=Kabrawala|first1=Shail|last2=Zimmer|first2=Margaret D.|last3=Campellone|first3=Kenneth G.|date=2020-01-14|title=WHIMP links the actin nucleation machinery to Src-family kinase signaling during protrusion and motility|url=https://www.biorxiv.org/content/10.1101/2020.01.14.906784v1|journal=bioRxiv|language=en|pages=2020.01.14.906784|doi=10.1101/2020.01.14.906784|doi-access=free}}</ref>

== Structure and function ==

The [[Wiskott–Aldrich syndrome|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 [[Stimulus (physiology)|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, central, 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 VVCA domain. It is located towards the C-terminal end of the protein and contains four motifs: two verprolin homology motifs (VV) binds actin monomers and delivers them to Arp2/3; the central domain (C) was once thought to bind cofilin but is now believed to enhance the interactions between the V domains and actin monomers, as well as the interaction between the A domain and Arp2/3; and the acidic motif (A) binds Arp2/3.<ref>{{cite journal | vauthors = Higgs HN, Pollard TD | title = Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins | journal = Annual Review of Biochemistry | volume = 70 | issue = 1 | pages = 649–76 | date = 2001 | pmid = 11395419 | doi = 10.1146/annurev.biochem.70.1.649 }}</ref> 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-WASp.<ref name=Prehoda_2000>{{cite journal | vauthors = Prehoda KE, Scott JA, Mullins RD, Lim WA | title = Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex | journal = Science | volume = 290 | issue = 5492 | pages = 801–6 | date = October 2000 | pmid = 11052943 | doi = 10.1126/science.290.5492.801 | bibcode = 2000Sci...290..801P }}</ref> 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.<ref name="Prehoda_2000"/> [[Cooperative binding]] of CDC42 and PIP2 relieve the autoinhibition of N-WASp, causing Arp2/3 to carry out actin polymerization.<ref name=Prehoda_2000/> 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.<ref name=Prehoda_2000/> 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.<ref name=Prehoda_2000/> 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.<ref>{{cite journal | vauthors = Rohatgi R, Ma L, Miki H, Lopez M, Kirchhausen T, Takenawa T, Kirschner MW | title = The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly | journal = Cell | volume = 97 | issue = 2 | pages = 221–31 | date = April 1999 | pmid = 10219243 | doi = 10.1016/S0092-8674(00)80732-1 | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Thrasher AJ, Burns SO | title = WASP: a key immunological multitasker | journal = Nature Reviews. Immunology | volume = 10 | issue = 3 | pages = 182–92 | date = March 2010 | pmid = 20182458 | doi = 10.1038/nri2724 | s2cid = 20764637 }}</ref> 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.<ref>{{cite web | title = Entrez Gene: WAS Wiskott-Aldrich syndrome (eczema-thrombocytopenia)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7454}}</ref>

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 [[infection]]s, and small-sized [[platelet]]s) in these patients the protein is usually significantly reduced or absent.   Other, less inactivating mutations affecting the ''WASp'' cause [[X-linked thrombocytopenia]], 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<ref name="WASP mutations">{{cite journal | vauthors = Rajmohan R, Raodah A, Wong MH, Thanabalu T | title = Characterization of Wiskott-Aldrich syndrome (WAS) mutants using Saccharomyces cerevisiae | journal = FEMS Yeast Research | volume = 9 | issue = 8 | pages = 1226–35 | date = December 2009 | pmid = 19817875 | doi = 10.1111/j.1567-1364.2009.00581.x | doi-access = free }}</ref> and these mutations affect binding with the WASp Interacting Protein.<ref name=WASP-WIP>{{cite journal | vauthors = Rajmohan R, Meng L, Yu S, Thanabalu T | title = WASP suppresses the growth defect of Saccharomyces cerevisiae las17Delta strain in the presence of WIP | journal = Biochemical and Biophysical Research Communications | volume = 342 | issue = 2 | pages = 529–36 | date = April 2006 | pmid = 16488394 | doi = 10.1016/j.bbrc.2006.01.160 }}</ref> Mutations located in the GBD domain disrupt autoinhibition and lead to an unfolded protein that is constitutively 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. This, in turn, causes myelodysplasia and X-linked neutropenia. 

A prospective gene therapy for Wiskott–Aldrich syndrome, [[OTL-103]], uses [[Autologous blood therapy|autologous]] [[CD34|CD34+]] lymphocytes that are transfected with a [[Lentiviral vector in gene therapy|lentiviral vector]] to produce functional WASp.<ref>{{Cite web | author = Orchard Therapeutics (Europe) Limited|date=2019-07-29|title=Orchard Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted for OTL-103 for the Treatment of Wiskott-Aldrich Syndrome|url=https://www.globenewswire.com/news-release/2019/07/29/1892716/0/en/Orchard-Therapeutics-Announces-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-Granted-for-OTL-103-for-the-Treatment-of-Wiskott-Aldrich-Syndrome.html|access-date=2021-06-28|website=GlobeNewswire News Room|language=en}}</ref> {{As of|2021|June|28}}, OTL-103 was undergoing [[Phases of clinical research|Phase I/II]] clinical trials at the [[San Raffaele Hospital]] in [[Milan|Milan, Italy]].<ref>{{ClinicalTrialsGov|NCT03837483|A Single Arm, Open-label Clinical Trial of Hematopoietic Stem Cell Gene Therapy With Cryopreserved Autologous CD34+ Cells Transduced With Lentiviral Vector Encoding WAS cDNA in Subjects With Wiskott-Aldrich Syndrome (WAS)}}}</ref>

== Interactions ==

Wiskott–Aldrich syndrome protein has been shown to [[Protein–protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[CDC42]],<ref name = pmid10713100>{{cite journal | vauthors = Tian L, Nelson DL, Stewart DM | title = Cdc42-interacting protein 4 mediates binding of the Wiskott-Aldrich syndrome protein to microtubules | journal = The Journal of Biological Chemistry | volume = 275 | issue = 11 | pages = 7854–61 | date = March 2000 | pmid = 10713100 | doi = 10.1074/jbc.275.11.7854 | doi-access = free }}</ref><ref name = pmid10724160>{{cite journal | vauthors = Kim AS, Kakalis LT, Abdul-Manan N, Liu GA, Rosen MK | title = Autoinhibition and activation mechanisms of the Wiskott-Aldrich syndrome protein | journal = Nature | volume = 404 | issue = 6774 | pages = 151–8 | date = March 2000 | pmid = 10724160 | doi = 10.1038/35004513 | bibcode = 2000Natur.404..151K | s2cid = 4416185 }}</ref><ref name = pmid8643625>{{cite journal | vauthors = Kolluri R, Tolias KF, Carpenter CL, Rosen FS, Kirchhausen T | title = Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 11 | pages = 5615–8 | date = May 1996 | pmid = 8643625 | pmc = 39296 | doi = 10.1073/pnas.93.11.5615 | bibcode = 1996PNAS...93.5615K | doi-access = free }}</ref><ref name = pmid8625410>{{cite journal | vauthors = Symons M, Derry JM, Karlak B, Jiang S, Lemahieu V, Mccormick F, Francke U, Abo A | title = Wiskott-Aldrich syndrome protein, a novel effector for the GTPase CDC42Hs, is implicated in actin polymerization | journal = Cell | volume = 84 | issue = 5 | pages = 723–34 | date = March 1996 | pmid = 8625410 | doi = 10.1016/S0092-8674(00)81050-8 | doi-access = free }}</ref> 
* [[CRKL]],<ref name = pmid11313252>{{cite journal | vauthors = Oda A, Ochs HD, Lasky LA, Spencer S, Ozaki K, Fujihara M, Handa M, Ikebuchi K, Ikeda H | title = CrkL is an adapter for Wiskott-Aldrich syndrome protein and Syk | journal = Blood | volume = 97 | issue = 9 | pages = 2633–9 | date = May 2001 | pmid = 11313252 | doi = 10.1182/blood.v97.9.2633 | doi-access = free }}</ref>
* [[Epidermal growth factor receptor|EGFR]],<ref name = pmid9307968/> 
* [[FGR (gene)|FGR]],<ref name = pmid8805332/><ref name = pmid8824280/><ref name = pmid7565724/> 
* [[FYN]],<ref name = pmid8805332/><ref name = pmid7565724/><ref name = pmid10532312>{{cite journal | vauthors = Banin S, Gout I, Brickell P | title = Interaction between Wiskott-Aldrich Syndrome protein (WASP) and the Fyn protein-tyrosine kinase | journal = Molecular Biology Reports | volume = 26 | issue = 3 | pages = 173–7 | date = August 1999 | pmid = 10532312 | doi = 10.1023/A:1006954206151 | s2cid = 36018089 }}</ref> 
* [[Grb2]],<ref name = pmid9307968>{{cite journal | vauthors = She HY, Rockow S, Tang J, Nishimura R, Skolnik EY, Chen M, Margolis B, Li W | title = Wiskott-Aldrich syndrome protein is associated with the adapter protein Grb2 and the epidermal growth factor receptor in living cells | journal = Molecular Biology of the Cell | volume = 8 | issue = 9 | pages = 1709–21 | date = September 1997 | pmid = 9307968 | pmc = 305731 | doi = 10.1091/mbc.8.9.1709 }}</ref><ref name = pmid8805332/> 
* [[ITK (gene)|ITK]]<ref name = pmid8892607>{{cite journal | vauthors = Cory GO, MacCarthy-Morrogh L, Banin S, Gout I, Brickell PM, Levinsky RJ, Kinnon C, Lovering RC | title = Evidence that the Wiskott-Aldrich syndrome protein may be involved in lymphoid cell signaling pathways | journal = Journal of Immunology | volume = 157 | issue = 9 | pages = 3791–5 | date = November 1996 | doi = 10.4049/jimmunol.157.9.3791 | pmid = 8892607 | doi-access = free }}</ref><ref name = pmid8810341>{{cite journal | vauthors = Bunnell SC, Henry PA, Kolluri R, Kirchhausen T, Rickles RJ, Berg LJ | title = Identification of Itk/Tsk Src homology 3 domain ligands | journal = The Journal of Biological Chemistry | volume = 271 | issue = 41 | pages = 25646–56 | date = October 1996 | pmid = 8810341 | doi = 10.1074/jbc.271.41.25646 | doi-access = free }}</ref> 
* [[ITSN2]],<ref name = pmid11748279>{{cite journal | vauthors = McGavin MK, Badour K, Hardy LA, Kubiseski TJ, Zhang J, Siminovitch KA | title = The intersectin 2 adaptor links Wiskott Aldrich Syndrome protein (WASp)-mediated actin polymerization to T cell antigen receptor endocytosis | journal = The Journal of Experimental Medicine | volume = 194 | issue = 12 | pages = 1777–87 | date = December 2001 | pmid = 11748279 | pmc = 2193569 | doi = 10.1084/jem.194.12.1777 }}</ref> 
* [[NCK1]],<ref name = pmid7565724>{{cite journal | vauthors = Rivero-Lezcano OM, Marcilla A, Sameshima JH, Robbins KC | title = Wiskott-Aldrich syndrome protein physically associates with Nck through Src homology 3 domains | journal = Molecular and Cellular Biology | volume = 15 | issue = 10 | pages = 5725–31 | date = October 1995 | pmid = 7565724 | pmc = 230823 | doi =  10.1128/MCB.15.10.5725}}</ref><ref name = pmid10747096>{{cite journal | vauthors = Krause M, Sechi AS, Konradt M, Monner D, Gertler FB, Wehland J | title = 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 | journal = The Journal of Cell Biology | volume = 149 | issue = 1 | pages = 181–94 | date = April 2000 | pmid = 10747096 | pmc = 2175102 | doi = 10.1083/jcb.149.1.181 }}</ref><ref name = pmid12135674>{{cite journal | vauthors = Okabe S, Fukuda S, Broxmeyer HE | title = 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 | journal = Experimental Hematology | volume = 30 | issue = 7 | pages = 761–6 | date = July 2002 | pmid = 12135674 | doi = 10.1016/s0301-472x(02)00823-8 | doi-access = free }}</ref> 
* [[PIK3R1]],<ref name = pmid8805332/> 
* [[PLCG1]],<ref name = pmid8805332>{{cite journal | vauthors = Banin S, Truong O, Katz DR, Waterfield MD, Brickell PM, Gout I | title = Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases | journal = Current Biology | volume = 6 | issue = 8 | pages = 981–8 | date = August 1996 | pmid = 8805332 | doi = 10.1016/s0960-9822(02)00642-5 | doi-access = free }}</ref><ref name = pmid8824280>{{cite journal | vauthors = Finan PM, Soames CJ, Wilson L, Nelson DL, Stewart DM, Truong O, Hsuan JJ, Kellie S | title = Identification of regions of the Wiskott-Aldrich syndrome protein responsible for association with selected Src homology 3 domains | journal = The Journal of Biological Chemistry | volume = 271 | issue = 42 | pages = 26291–5 | date = October 1996 | pmid = 8824280 | doi = 10.1074/jbc.271.42.26291 | doi-access = free }}</ref> 
* [[PSTPIP1]],<ref name = pmid9488710>{{cite journal | vauthors = Wu Y, Spencer SD, Lasky LA | title = Tyrosine phosphorylation regulates the SH3-mediated binding of the Wiskott-Aldrich syndrome protein to PSTPIP, a cytoskeletal-associated protein | journal = The Journal of Biological Chemistry | volume = 273 | issue = 10 | pages = 5765–70 | date = March 1998 | pmid = 9488710 | doi = 10.1074/jbc.273.10.5765 | doi-access = free }}</ref> 
* [[Src (gene)|Src]],<ref name = pmid8805332/><ref name = pmid8824280/> 
* [[TRIP10]],<ref name = pmid10713100/> and
* [[WIPF1]].<ref name = pmid9405671>{{cite journal | vauthors = Ramesh N, Antón IM, Hartwig JH, Geha RS | title = WIP, a protein associated with wiskott-aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 26 | pages = 14671–6 | date = December 1997 | pmid = 9405671 | pmc = 25088 | doi = 10.1073/pnas.94.26.14671 | bibcode = 1997PNAS...9414671R | doi-access = free }}</ref><ref name = pmid9694849>{{cite journal | vauthors = Antón IM, Lu W, Mayer BJ, Ramesh N, Geha RS | title = The Wiskott-Aldrich syndrome protein-interacting protein (WIP) binds to the adaptor protein Nck | journal = The Journal of Biological Chemistry | volume = 273 | issue = 33 | pages = 20992–5 | date = August 1998 | pmid = 9694849 | doi = 10.1074/jbc.273.33.20992 | doi-access = free }}</ref> 
{{Div col end}}

== See also ==
*[[WASL (gene)|Wiskott–Aldrich syndrome-like]]
*[[cortactin]]
{{Clear}}

== References ==
{{Reflist|35em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = O'Sullivan E, Kinnon C, Brickell P | title = Wiskott-Aldrich syndrome protein, WASP | journal = The International Journal of Biochemistry & Cell Biology | volume = 31 | issue = 3–4 | pages = 383–7 | year = 1999 | pmid = 10224664 | doi = 10.1016/S1357-2725(98)00118-6 }}
* {{cite journal | vauthors = Snapper SB, Rosen FS | title = The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization | journal = Annual Review of Immunology | volume = 17 | pages = 905–29 | year = 1999 | pmid = 10358777 | doi = 10.1146/annurev.immunol.17.1.905 }}
* {{cite journal | vauthors = Thrasher AJ, Kinnon C | title = The Wiskott-Aldrich syndrome | journal = Clinical and Experimental Immunology | volume = 120 | issue = 1 | pages = 2–9 | date = April 2000 | pmid = 10759756 | pmc = 1905602 | doi = 10.1046/j.1365-2249.2000.01193.x }}
{{refend}}

== External links ==
{{Commons category|Wiskott-Aldrich syndrome}}
*[https://www.ncbi.nlm.nih.gov/books/NBK1178/ GeneReviews/NIH/NCBI/UW entry on ''WAS''-Related Disorders including Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN)]
*{{OMIM|300392}}
*{{OMIM|313900}}
*{{MeshName|Wiskott-Aldrich+Syndrome+Protein}}
* {{PDBe-KB2|P42768|Wiskott-Aldrich syndrome protein}}

{{PDB Gallery|geneid=7454}}
{{Cytoskeletal Proteins}}