Wiskott–Aldrich syndrome protein
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The Wiskott–Aldrich Syndrome protein (WASp) is a 502-
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
protein expressed in cells of the hematopoietic system that in humans is encoded by the ''WAS''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. In the inactive state, WASp exists in an autoinhibited conformation with sequences near its
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
binding to a region near its
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
. Its activation is dependent upon CDC42 and
PIP2 Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...
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 Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most actin cytoskeleton- ...
. Activated Arp2/3
nucleate In thermodynamics, nucleation is the first step in the formation of either a new thermodynamic phase or structure via self-assembly or self-organization within a substance or mixture. Nucleation is typically defined to be the process that dete ...
s new F-
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
. WASp is the founding member of a gene family which also includes the broadly expressed
N-WASP Neural Wiskott-Aldrich syndrome protein is a protein that in humans is encoded by the ''WASL'' gene. The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors ...
(neuronal Wiskott–Aldrich Syndrome protein),
SCAR A scar (or scar tissue) is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a na ...
/ WAVE1,
WASH WASH (or Watsan, WaSH) is an acronym that stands for "water, sanitation and hygiene". It is used widely by non-governmental organizations and aid agencies in developing countries. The purposes of providing access to WASH services include achievin ...
, WHAMM, and JMY. WAML (WASP and MIM like), WAWH (WASP without WH1 domain), and WHIMP (WAVE Homology in Membrane Protrusions) have more recently been discovered.


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 A stimulus is something that causes a physiological response. It may refer to: * Stimulation ** Stimulus (physiology), something external that influences an activity ** Stimulus (psychology), a concept in behaviorism and perception * Stimulus (eco ...
, and interact with multiple proteins. These proteins, directly or indirectly, associate with the small
GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
CDC42, known to regulate formation of actin filaments, and the cytoskeletal organising complex,
Arp2/3 Arp2/3 complex (Actin Related Protein 2/3 complex) is a seven-subunit protein complex that plays a major role in the regulation of the actin cytoskeleton. It is a major component of the actin cytoskeleton and is found in most actin cytoskeleton- ...
. 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. 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. 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 Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczem ...
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 Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
,
eczema Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can ...
, recurrent
infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...
s, and small-sized
platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
s) in these patients the protein is usually significantly reduced or absent. Other, less inactivating mutations affecting the ''WASp'' cause
X-linked thrombocytopenia X-linked thrombocytopenia, also referred to as XLT or thrombocytopenia 1, is an inherited clotting disorder that primarily affects males. It is a ''WAS''-related disorder, meaning it is caused by a mutation in the Wiskott–Aldrich syndrome (''WAS ...
, 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 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 OTL-103 (GSK-2696275) is a gene therapy for Wiskott–Aldrich syndrome, a rare primary immunodeficiency caused by mutations in the gene that codes for Wiskott–Aldrich syndrome protein (WASp). It was developed by Orchard Therapeutics in conjunc ...
, uses
autologous Autotransplantation is the transplantation of organs, tissues, or even particular proteins from one part of the body to another in the same person ('' auto-'' meaning "self" in Greek). The autologous tissue (also called autogenous, autogene ...
CD34+ lymphocytes that are transfected with a
lentiviral vector Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cell (biology), cells. This process can be performed inside a living organism (''in vivo'') or in cell culture (''in vitro''). Viruses have evolved spec ...
to produce functional WASp. , OTL-103 was undergoing Phase I/II clinical trials at the
San Raffaele Hospital The San Raffaele Hospital (also ''Istituto scientifico universitario San Raffaele'' or ''ospedale San Raffaele'', ''HSR'' or ''OSR'') is a university hospital situated in Segrate, the Province of Milan, Italy. It was founded in 1969 by don Luigi ...
in
Milan, Italy Milan ( , , Lombard language, Lombard: ; it, Milano ) is a city in northern Italy, capital of Lombardy, and the List of cities in Italy, second-most populous city proper in Italy after Rome. The city proper has a population of about 1.4  ...
.}


Interactions

Wiskott–Aldrich syndrome protein has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: * CDC42, *
CRKL Crk-like protein is a protein that in humans is encoded by the CRKL gene. Function v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pathw ...
, * EGFR, * FGR, *
FYN Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
, * Grb2, *
ITK Itk is a framework for building mega-widgets using the Incr Tcl incr Tcl (commonly stylised as '' ncr Tcl/nowiki>'', and often abbreviated to ''itcl'') is a set of object-oriented extensions for the Tcl programming language. It is widely us ...
*
ITSN2 Intersectin-2 is a protein that in humans is encoded by the ''ITSN2'' gene. This gene encodes a cytoplasmic protein which contains SH3 domains. This protein is a member of a family of proteins involved in clathrin-mediated endocytosis. Intersecti ...
, *
NCK1 Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene. Gene The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from ...
, *
PIK3R1 Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the ''PIK3R1'' gene. Function Phosphatidylinositol 3-kinase phosphorylates the inositol ring of phosphatidylinositol at the 3-prime position. The e ...
, *
PLCG1 Phospholipase C, gamma 1, also known as PLCG1,is a protein that in humans involved in cell growth, migration, apoptosis, and proliferation. It is encoded by the ''PLCG1'' gene and is part of the PLC superfamily. Function PLCγ1 is a cell grow ...
, *
PSTPIP1 Proline-serine-threonine phosphatase-interacting protein 1 is an enzyme that in humans is encoded by the ''PSTPIP1'' gene. Interactions PSTPIP1 has been shown to interact with: * Abl gene, * BZW1, * CD2, * PTPN12, * PTPN18, and * Wisko ...
, * Src, *
TRIP10 Cdc42-interacting protein 4 is a protein that in humans is encoded by the ''TRIP10'' gene. Interactions TRIP10 has been shown to interact with STAT3, Wiskott-Aldrich syndrome protein, Huntingtin, CDC42, AKAP9 and RHOQ Rho-related GTP-bindi ...
, and *
WIPF1 WAS/WASL-interacting protein (WIP) is a protein that in humans is encoded by the ''WIPF1'' gene. Function This gene encodes a protein that plays an important role in the organization of the actin cytoskeleton. Overexpression of WIP in mammalia ...
.


See also

* Wiskott–Aldrich syndrome-like *
cortactin Cortactin (from "''cortical actin'' binding protein") is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin c ...


References


Further reading

* * *


External links


GeneReviews/NIH/NCBI/UW entry on ''WAS''-Related Disorders including Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked congenital neutropenia (XLN)
* * * * {{Cytoskeletal Proteins