Wiskott–Aldrich syndrome protein

Source: Wikipedia, the free encyclopedia.

WAS
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000015285

ENSMUSG00000031165

UniProt

P42768

P70315

RefSeq (mRNA)

NM_000377

NM_009515

RefSeq (protein)

NP_000368
NP_000368.1

NP_033541

Location (UCSC)Chr X: 48.68 – 48.69 MbChr X: 7.95 – 7.96 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The Wiskott–Aldrich syndrome protein (WASp) is a 502-

nucleates new F-actin
.

WASp is the founding member of a gene family which also includes the broadly expressed

WAVE1, WASH, WHAMM, and JMY.[5][6] WAML (WASP and MIM like), WAWH (WASP without WH1 domain), and WHIMP (WAVE Homology in Membrane Protrusions) have more recently been discovered.[7][8]

Structure and function

The

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.[9] 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.[10] 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.[10] Cooperative binding of CDC42 and PIP2 relieve the autoinhibition of N-WASp, causing Arp2/3 to carry out actin polymerization.[10] 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.[10] 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.[10] 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.[11]

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.[12] 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.[13]

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

eczema, recurrent infections, and small-sized platelets) 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[14] and these mutations affect binding with the WASp Interacting Protein.[15]
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 CD34+ lymphocytes that are transfected with a lentiviral vector to produce functional WASp.[16] As of 28 June 2021, OTL-103 was undergoing Phase I/II clinical trials at the San Raffaele Hospital in Milan, Italy.[17]

Interactions

Wiskott–Aldrich syndrome protein has been shown to interact with:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000015285 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031165 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 19625501
    .
  6. PMID 23291261
    .
  7. PMID 23499790
    .
  8. doi:10.1101/2020.01.14.906784
    .
  9. PMID 11395419
    .
  10. ^
    PMID 11052943
    .
  11. PMID 10219243
    .
  12. S2CID 20764637
    .
  13. ^ "Entrez Gene: WAS Wiskott-Aldrich syndrome (eczema-thrombocytopenia)".
  14. PMID 19817875
    .
  15. PMID 16488394
    .
  16. ^ Orchard Therapeutics (Europe) Limited (29 July 2019). "Orchard Therapeutics Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted for OTL-103 for the Treatment of Wiskott-Aldrich Syndrome". GlobeNewswire News Room. Retrieved 28 June 2021.
  17. ^ Clinical trial number NCT03837483 for "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)" at ClinicalTrials.gov}
  18. ^
    PMID 10713100
    .
  19. S2CID 4416185
    .
  20. PMID 8643625
    .
  21. PMID 8625410
    .
  22. PMID 11313252
    .
  23. ^
    PMID 9307968
    .
  24. ^
    PMID 8805332
    .
  25. ^
    PMID 8824280
    .
  26. ^
    PMID 7565724
    .
  27. S2CID 36018089
    .
  28. PMID 8892607
    .
  29. PMID 8810341
    .
  30. PMID 11748279
    .
  31. PMID 10747096
    .
  32. PMID 12135674
    .
  33. PMID 9488710
    .
  34. PMID 9405671
    .
  35. PMID 9694849
    .

Further reading

External links

Wikimedia Commons has media related to Wiskott-Aldrich syndrome.
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