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PDB 1cee

Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott-Aldrich syndrome’ protein. Cdc42. WASP. PDB 1cee. List. Finish Breast Cancer Talk Look up Drugs affecting WAS and structures Conclusion/ WAS Write whole speech PRACTICE PRACTICE PRACTICe

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PDB 1cee

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  1. Structure of Cdc42 in complex with the GTPase-binding domain of the ‘Wiskott-Aldrich syndrome’ protein Cdc42 WASP PDB 1cee

  2. List • Finish Breast Cancer Talk • Look up Drugs affecting WAS and structures • Conclusion/ WAS • Write whole speech • PRACTICE PRACTICE PRACTICe • Tuesday, 10-12 Eagleton Institute of Politics • 1-4:30 I have 3 1/2 hours

  3. Overview Introduction Function Structure Disease Treatment Conclusion

  4. Introduction • CDC42 is a member of a small family of GTPases. Through the action of GTPases, GTP (an essential for signal transduction with G-proteins) is converted to GDP (guanosine diphosphate). • GTP-binding proteins together control the assembly, organization, and disassembly of the actin cytoskeleton in response to extracellular signals in eukaryotic cells. • The Cdc42 proteins bind to effector proteins • Diseases such as the Wiskott- Aldrich Syndrome or certain forms of cancer,such as breast cancer are thought to arise due to derangement or mutations of the Cdc42.

  5. Function “Cdc42 acts as a molecular switch in signaling pathways that regulate cytoskeletal architecture, gene expression, and progression of the cell cycle. The switch transmits different signals through the GTP-dependent binding to effector proteins containing a Cdc42/Rac interactive binding (CRIB) motif”

  6. Regulators of the actin cytoskeleton Control motility of mammalian cells Transduce signals from extracellular stimuli to intracellular signal transduction pathways. Function

  7. Signaling Pathway Involving Cdc42 Cdc42 Re Cdc42 GDP GTPase Cycle Cdc42 GTP Effectors WASP Regulates Actin cytoskeleton Cell morphology Cell migration Cell growth Cell survival Gene expression

  8. Structure (By NMR Spectroscopy) Structure of the Cdc42 complex binding through GTP-dependent binding to effector proteins containing a Cdc42/Rac interactive-binding (CRIB) motif. • Chain A : GTP-binding Rho-like Protein • Chain B is the Wiskott-Aldrich Syndrome Protein • Fifty-five known interactions • The CDC42/Rac- binding domain is between amino acids 201-321 on WASP.

  9. Chain B: WASP CRIB Motif Chain A: Cdc42 PDB 1cee

  10. C Switch I Switch II N ß3 ß2 C CRIB N PDB 1cee

  11. Structure Cdc42 residues Phe37, Asn39 and Ala41, near the C terminus of switch I, form main-chain hydrogen bonds to WASP residues Val250, Val247/Ser 248 and Lys 245. These interactions position the Asp38 side chain of Cdc42 near WASP residues His246 and His249. There is a hydrogen bond from the Asp 38 to eiter His 246 or His249 ring.

  12. C Switch I Switch II N ß3 ß2 C CRIB N PDB 1cee

  13. I276 V36 L67 A274 V260 F271 D38 F37 L70 L270 H249 Y40 I21 L267 F56 T25 H246 PDB 1cee

  14. WASP H249 D38 F56 Hydrogen Bonds Y40 H246 I21 Cdc42

  15. Structure • Hydrophobic interactions anchor WASP residues 232-238 to the Cdc42 B2/B3 hairpin and alpha 5 helix. • Interaction of the WASP GBD N terminus and the Cdc42 B2/ B3 hairpin and alpha5 helix.

  16. C Switch I Switch II N ß3 ß2 C CRIB N PDB 1cee

  17. Y51 I46 I238 D237 I233 I173 L177 L174 K235

  18. Y51 I46 I173 L177 Hydrogen Bonds D237 K235 E174 PDB 1cee

  19. Gene Sequence Binding Preference Rac Cdc42 CRIB motif Switch I 48 59 Switch II 75 168 178 30

  20. Wiskott- Aldrich Syndrome • Rare X-lined recessive disorder that affects cell morphology and signal transduction in hematopoietic cells • Function of WASP is to serve as a bridge between signaling and movement of the actin filaments in the cytoskeleton. • Researchers identified many different mutations that interfere with the protein binding to Cdc42, which is involved in regulation of the actin cytoskeleton of lymphocytes. The actin cytoskeleton is responsible for cellular functions such as growth, endocytosis, exocytosis, and cytokinesis. • Human mutations in WASP cause several defects in haematopoletic cell function • Other research has shown that the Cdc42-WASp reaction is necessary for cetain chemoattractant-induced T-cell chemotaxis. • Linked absent WASP expression to classic WAS • Mutant WASP expression to X-linked thrombocytopenia, and WASP with missens mutations at the Cdc42 binding site to X-linked neutropenia.

  21. Interaction • Show surface depiction of interaction • Look for mutated ones

  22. Drugs used and structures

  23. Treatment • WAS is treated with a variety of therapeutic agents including antibiotics, antivirals, antifungals, chemotherapeutic agents, immunoglobulins, and corticosteroids. • Examples: Prednisone, Methylprednisolone, fluocinolone, and immune globulin.

  24. Conclusion

  25. References

  26. Questions/Comments?

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