| Structural highlights
Function
[ARAP3_HUMAN] Phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating protein that modulates actin cytoskeleton remodeling by regulating ARF and RHO family members. Is activated by phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) binding. Can be activated by phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding, albeit with lower efficiency. Acts on ARF6, RAC1, RHOA and CDC42. Plays a role in the internalization of anthrax toxin.[1] [2]
Publication Abstract from PubMed
ARAP3 (Arf-GAP with Rho-GAP domain, ANK repeat, and PH domain-containing protein 3) is unique for its dual specificity GAPs (GTPase-activating protein) activity for Arf6 (ADP-ribosylation factor 6) and RhoA (Ras homolog gene family member A) regulated by phosphatidylinositol 3,4,5-trisphosphate and a small GTPase Rap1-GTP and is involved in regulation of cell shape and adhesion. However, the molecular interface between the ARAP3-RhoGAP domain and RhoA is unknown, as is the substrates specificity of the RhoGAP domain. In this study, we solved the crystal structure of RhoA in complex with the RhoGAP domain of ARAP3. The structure of the complex presented a clear interface between the RhoGAP domain and RhoA. By analyzing the crystal structure and in combination with in vitro GTPase activity assays and isothermal titration calorimetry experiments, we identified the crucial residues affecting RhoGAP activity and substrates specificity among RhoA, Rac1 (Ras-related C3 botulinum toxin substrate 1), and Cdc42 (cell division control protein 42 homolog).
Structural Basis for the Specific Recognition of RhoA by the Dual GTPase-activating Protein ARAP3.,Bao H, Li F, Wang C, Wang N, Jiang Y, Tang Y, Wu J, Shi Y J Biol Chem. 2016 Aug 5;291(32):16709-19. doi: 10.1074/jbc.M116.736140. Epub 2016, Jun 15. PMID:27311713[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Krugmann S, Anderson KE, Ridley SH, Risso N, McGregor A, Coadwell J, Davidson K, Eguinoa A, Ellson CD, Lipp P, Manifava M, Ktistakis N, Painter G, Thuring JW, Cooper MA, Lim ZY, Holmes AB, Dove SK, Michell RH, Grewal A, Nazarian A, Erdjument-Bromage H, Tempst P, Stephens LR, Hawkins PT. Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. Mol Cell. 2002 Jan;9(1):95-108. PMID:11804589
- ↑ Lu Q, Wei W, Kowalski PE, Chang AC, Cohen SN. EST-based genome-wide gene inactivation identifies ARAP3 as a host protein affecting cellular susceptibility to anthrax toxin. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17246-51. Epub 2004 Nov 29. PMID:15569923 doi:http://dx.doi.org/10.1073/pnas.0407794101
- ↑ Bao H, Li F, Wang C, Wang N, Jiang Y, Tang Y, Wu J, Shi Y. Structural Basis for the Specific Recognition of RhoA by the Dual GTPase-activating Protein ARAP3. J Biol Chem. 2016 Aug 5;291(32):16709-19. doi: 10.1074/jbc.M116.736140. Epub 2016, Jun 15. PMID:27311713 doi:http://dx.doi.org/10.1074/jbc.M116.736140
|
