# WAS

## Overview
The WAS gene encodes the Wiskott-Aldrich Syndrome Protein (WASP), a critical actin nucleation promoting factor involved in the regulation of the actin cytoskeleton. WASP is primarily expressed in hematopoietic cells and plays a pivotal role in various cellular processes, including cell signaling, movement, and immune responses. The protein is characterized by its modular structure, which includes domains that facilitate interactions with other proteins and regulatory molecules, enabling it to control actin polymerization through the Arp2/3 complex (Padrick2010Physical; Thrasher2010WASP:). Mutations in the WAS gene can lead to Wiskott-Aldrich syndrome, a condition marked by immunodeficiency and other clinical manifestations (Houmadi2018The). WASP's function and regulation are critical for maintaining normal cellular activities, and its dysregulation is associated with various pathologies, including hematopoietic malignancies (Biber2021Targeting).

## Structure
The Wiskott-Aldrich Syndrome Protein (WASP) is characterized by a modular structure that facilitates its role in actin cytoskeleton reorganization. The primary structure of WASP includes several key domains: the WH1 domain, a basic region, a GTPase-binding domain (GBD), a proline-rich region, and a VCA domain (Padrick2010Physical; Thrasher2010WASP:). The GBD contains a CRIB motif essential for binding to the GTPase Cdc42, which regulates WASP activity by disrupting its autoinhibited state (Kim2000Autoinhibition; AbdulManan1999Structure).

The secondary structure of WASP involves alpha helices and beta sheets, with the GBD forming a globular domain that includes a short beta-hairpin and several alpha-helices (Kim2000Autoinhibition). The tertiary structure is stabilized by hydrophobic and electrostatic interactions, particularly within the GBD, which sequesters the VCA domain in the autoinhibited state (Kim2000Autoinhibition).

WASP can form quaternary structures through interactions with other proteins, such as the Arp2/3 complex, which is crucial for actin nucleation (Padrick2010Physical). Post-translational modifications, including phosphorylation, play a significant role in regulating WASP activity, particularly at tyrosine residue 291 (Kim2000Autoinhibition). Splice variants of WASP result in different isoforms, which may have distinct functions (Thrasher2010WASP:).

## Function
The WAS gene encodes the Wiskott-Aldrich Syndrome Protein (WASP), which plays a crucial role in actin cytoskeleton remodeling, a process essential for various cellular functions. WASP is a key regulator of the Arp2/3 complex, which initiates the formation of branched actin filament networks. This activity is vital for the development of actin-based structures such as lamellipodia and filopodia, which are important for cell movement and morphology (Pollitt2009WASP; Rodnick-Smith2016Role).

WASP proteins are typically found in an autoinhibited state, which is relieved by interactions with the small GTPase Cdc42 and phospholipids like PtdIns(4,5)P2, allowing them to activate the Arp2/3 complex and promote actin nucleation (Pollitt2009WASP; Stradal2004Regulation). This activation involves a conformational change in the Arp2/3 complex, which is crucial for nucleating new actin filaments (Rodnick-Smith2016Role).

In addition to its role in actin assembly, WASP is involved in cellular processes such as membrane trafficking and endocytosis. It is recruited to sites of phagocytosis and interacts with proteins like dynamin to facilitate endocytosis (Pollitt2009WASP). WASP's activity is particularly significant in hematopoietic cells, where it influences immune cell functions and responses (Biber2021Targeting).

## Clinical Significance
Mutations in the WAS gene, which encodes the Wiskott-Aldrich Syndrome Protein (WASP), lead to Wiskott-Aldrich syndrome (WAS), a condition characterized by immunodeficiency, eczema, and thrombocytopenia. WASP is crucial for actin cytoskeleton reorganization, and its deficiency results in impaired immune cell function. In CD8+ cytotoxic T lymphocytes (CTLs), WASP deficiency leads to reduced LFA-1 activation, affecting the stability of the immunological synapse and reducing the ability to kill target cells effectively (Houmadi2018The). This deficiency also results in abnormal LFA-1 nanocluster distribution and impaired lytic granule positioning, further compromising CTL function (Houmadi2018The).

Altered WASP expression is also implicated in hematopoietic malignancies. High WASP expression correlates with shorter survival in patients with certain cancers, such as lymphoblastic acute myeloid leukemia (LAML) (Biber2021Targeting). Targeting WASP with small molecule compounds like SMC #13, which promotes its degradation, has been explored as a therapeutic strategy for these malignancies. This approach disrupts cytoskeletal dynamics crucial for cancer cell functions, potentially reducing proliferation and migration of malignant cells (Biber2021Targeting).

## Interactions
The Wiskott-Aldrich syndrome protein (WASP) is involved in various interactions that regulate actin polymerization and cytoskeletal dynamics. WASP specifically interacts with the GTPase CDC42Hs, a member of the Rho family, which is crucial for actin cytoskeleton dynamics, including the formation of filopodia and lamellipodia (Symons1996Wiskott–Aldrich). This interaction is mediated through the GTPase-binding domain (GBD) of WASP, which is necessary for binding to CDC42Hs and is essential for WASP's role as an effector in actin polymerization (Symons1996Wiskott–Aldrich).

WASP also interacts with SH3 domain-containing proteins such as NCK, which suggests a role in tyrosine kinase signaling pathways (Symons1996Wiskott–Aldrich). The proline-rich regions in WASP facilitate these interactions, allowing it to bind to proteins like profilin and VASP, which are important for actin filament assembly (Symons1996Wiskott–Aldrich).

WASP's activity is regulated by its interaction with the WASP-interacting protein (WIP), which stabilizes WASP and directs it to areas of actin assembly. WIP protects WASP from degradation and maintains it in an autoinhibited conformation until specific signals are received (Antón2007WASP-interacting). These interactions are crucial for the regulation of actin dynamics and signaling specificity in cellular processes (Padrick2010Physical).


## References


[1. (Pollitt2009WASP) Alice Y. Pollitt and Robert H. Insall. Wasp and scar/wave proteins: the drivers of actin assembly. Journal of Cell Science, 122(15):2575–2578, August 2009. URL: http://dx.doi.org/10.1242/jcs.023879, doi:10.1242/jcs.023879. This article has 246 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.023879)

[2. (Rodnick-Smith2016Role) Max Rodnick-Smith, Qing Luan, Su-Ling Liu, and Brad J. Nolen. Role and structural mechanism of wasp-triggered conformational changes in branched actin filament nucleation by arp2/3 complex. Proceedings of the National Academy of Sciences, June 2016. URL: http://dx.doi.org/10.1073/pnas.1517798113, doi:10.1073/pnas.1517798113. This article has 48 citations.](https://doi.org/10.1073/pnas.1517798113)

[3. (Biber2021Targeting) Guy Biber, Aviad Ben-Shmuel, Elad Noy, Noah Joseph, Abhishek Puthenveetil, Neria Reiss, Omer Levy, Itay Lazar, Ariel Feiglin, Yanay Ofran, Meirav Kedmi, Abraham Avigdor, Sophia Fried, and Mira Barda-Saad. Targeting the actin nucleation promoting factor wasp provides a therapeutic approach for hematopoietic malignancies. Nature Communications, September 2021. URL: http://dx.doi.org/10.1038/s41467-021-25842-7, doi:10.1038/s41467-021-25842-7. This article has 9 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41467-021-25842-7)

[4. (AbdulManan1999Structure) Norzehan Abdul-Manan, Behzad Aghazadeh, Grace A. Liu, Ananya Majumdar, Ouathek Ouerfelli, Katherine A. Siminovitch, and Michael K. Rosen. Structure of cdc42 in complex with the gtpase-binding domain of the ‘wiskott–aldrich syndrome’ protein. Nature, 399(6734):379–383, May 1999. URL: http://dx.doi.org/10.1038/20726, doi:10.1038/20726. This article has 272 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/20726)

[5. (Padrick2010Physical) Shae B. Padrick and Michael K. Rosen. Physical mechanisms of signal integration by wasp family proteins. Annual Review of Biochemistry, 79(1):707–735, June 2010. URL: http://dx.doi.org/10.1146/annurev.biochem.77.060407.135452, doi:10.1146/annurev.biochem.77.060407.135452. This article has 278 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1146/annurev.biochem.77.060407.135452)

[6. (Antón2007WASP-interacting) Inés M. Antón, Gareth E. Jones, Francisco Wandosell, Raif Geha, and Narayanaswamy Ramesh. Wasp-interacting protein (wip): working in polymerisation and much more. Trends in Cell Biology, 17(11):555–562, November 2007. URL: http://dx.doi.org/10.1016/j.tcb.2007.08.005, doi:10.1016/j.tcb.2007.08.005. This article has 112 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.tcb.2007.08.005)

[7. (Kim2000Autoinhibition) Annette S. Kim, Lazaros T. Kakalis, Norzehan Abdul-Manan, Grace A. Liu, and Michael K. Rosen. Autoinhibition and activation mechanisms of the wiskott–aldrich syndrome protein. Nature, 404(6774):151–158, March 2000. URL: http://dx.doi.org/10.1038/35004513, doi:10.1038/35004513. This article has 549 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/35004513)

[8. (Symons1996Wiskott–Aldrich) Marc Symons, Jonathan M.J Derry, Brian Karlak, Sharon Jiang, Vanessa Lemahieu, Frank McCormick, Uta Francke, and Arie Abo. Wiskott–aldrich syndrome protein, a novel effector for the gtpase cdc42hs, is implicated in actin polymerization. Cell, 84(5):723–734, March 1996. URL: http://dx.doi.org/10.1016/s0092-8674(00)81050-8, doi:10.1016/s0092-8674(00)81050-8. This article has 698 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s0092-8674(00)81050-8)

[9. (Houmadi2018The) Raïssa Houmadi, Delphine Guipouy, Javier Rey-Barroso, Zilton Vasconcelos, Julie Cornet, Manoel Manghi, Nicolas Destainville, Salvatore Valitutti, Sophie Allart, and Loïc Dupré. The wiskott-aldrich syndrome protein contributes to the assembly of the lfa-1 nanocluster belt at the lytic synapse. Cell Reports, 22(4):979–991, January 2018. URL: http://dx.doi.org/10.1016/j.celrep.2017.12.088, doi:10.1016/j.celrep.2017.12.088. This article has 43 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.celrep.2017.12.088)

[10. (Thrasher2010WASP:) Adrian J. Thrasher and Siobhan O. Burns. Wasp: a key immunological multitasker. Nature Reviews Immunology, 10(3):182–192, March 2010. URL: http://dx.doi.org/10.1038/nri2724, doi:10.1038/nri2724. This article has 445 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/nri2724)

[11. (Stradal2004Regulation) Theresia E.B. Stradal, Klemens Rottner, Andrea Disanza, Stefano Confalonieri, Metello Innocenti, and Giorgio Scita. Regulation of actin dynamics by wasp and wave family proteins. Trends in Cell Biology, 14(6):303–311, June 2004. URL: http://dx.doi.org/10.1016/j.tcb.2004.04.007, doi:10.1016/j.tcb.2004.04.007. This article has 362 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.tcb.2004.04.007)