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case 22

immunology
by

Dilya Ibrasheva

on 27 April 2010

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Transcript of case 22

Case 22: Wiskott-Aldrich Syndrome

Question B

Dilya Ibrasheva & Noah Cohen The three-dimensional structure of the Wiskott-Aldrich protein (WASP), shown in magenta, bound to another protein, called WIP (blue), was determined using NMR spectroscopy by researchers in the MCW Interdisciplinary Program. Careful examination of the interactions between these two molecules revealed the molecular basis for Wiskott-Aldrich syndrome, an inherited disorder that causes serious defects in the function of blood cells. What is the molecular defect in Wiskott-Aldrich syndrome? WASP,a Wiskott-Aldrich syndrome protein, is a product of WAS gene, mutations of which can lead to Wiskott-Aldrich syndrome.
It is expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients Actin-related protein complex
Binding of it to VCA initiates the nucleation of F-actin
Guides the branching of the F-actin filaments during their polymerasation, which is necessary for production of new filaments Binds to the basic domain, forming a hairpin, which results in inactivation of WASP G protein After the small G protein Cdc42 binds to the G-protein-binding domain (GBD), WASP changes its conformation and becomes linear and active, which allows VCA domain to bind the Arp 2/3 WH1 binds WIP (the WASP interactive protein) that keeps WASP inactive until it is released from WASP binding What domains does this protein have? How do the domains relate to its function (what do the different domains interact with)? What processes does it affect in T cells? Any functions that depend on the actin cytoskeleton, its reorganization and cell signalling:

Interactions with B cells or other target cells

Movement (e.g. emigration from the thymus into the blood vessels and from the bloodstream into lymphoid tissue)

T cell activation induced cell division
References: Cotta-de-Almeida , V. et al., (2007). Wiskott aldrich syndrome protein (wasp) and n-wasp are critical for t cell development.. Proc Natl Acad Sci U S A. , 104(39):15424-9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17878299

Jin, Y. et al., (2004). Mutations of the wiskott-aldrich syndrome protein (wasp): hotspots, effect on transcription, and translation and phenotype/genotype correlation . Blood, 104(13), Retrieved from http://bloodjournal.hematologylibrary.org/cgi/content/long/104/13/4010 doi: 10.1182/blood-2003-05-1592. http://www.mcw.edu/FileLibrary/User/jpokorny/IDP/focus/3DwaspProtein.jpg proline-rich region with SH3 binding motifs
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