Structural highlights4q9u is a 8 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Related: | 4n3x, 4n3y, 4n3z |
| Gene: | RABGEF1, RABEX5 (HUMAN), RAB5A, RAB5 (HUMAN), RABEP1, RAB5EP, RABPT5, RABPT5A (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function[RABX5_HUMAN] Rab effector protein acting as linker between gamma-adaptin, RAB4A or RAB5A. Involved in endocytic membrane fusion and membrane trafficking of recycling endosomes. Stimulates nucleotide exchange on RAB5A. Can act as a ubiquitin ligase (By similarity).[1] [2] [3] [RABE1_HUMAN] Rab effector protein acting as linker between gamma-adaptin, RAB4A and RAB5A. Involved in endocytic membrane fusion and membrane trafficking of recycling endosomes. Stimulates RABGEF1 mediated nucleotide exchange on RAB5A.[4] [5] [6] [7] [RAB5A_HUMAN] Required for the fusion of plasma membranes and early endosomes. Contributes to the regulation of filopodia extension.[8]
Publication Abstract from PubMed
Rabex-5 and Rabaptin-5 function together to activate Rab5 and further promote early endosomal fusion in endocytosis. The Rabex-5 GEF activity is autoinhibited by the Rabex-5 CC domain (Rabex-5CC) and activated by the Rabaptin-5 C2-1 domain (Rabaptin-5C21) with yet unknown mechanism. We report here the crystal structures of Rabex-5 in complex with the dimeric Rabaptin-5C21 (Rabaptin-5C212) and in complex with Rabaptin-5C212 and Rab5, along with biophysical and biochemical analyses. We show that Rabex-5CC assumes an amphipathic alpha-helix which binds weakly to the substrate-binding site of the GEF domain, leading to weak autoinhibition of the GEF activity. Binding of Rabaptin-5C21 to Rabex-5 displaces Rabex-5CC to yield a largely exposed substrate-binding site, leading to release of the GEF activity. In the ternary complex the substrate-binding site of Rabex-5 is completely exposed to bind and activate Rab5. Our results reveal the molecular mechanism for the regulation of the Rabex-5 GEF activity.
Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5.,Zhang Z, Zhang T, Wang S, Gong Z, Tang C, Chen J, Ding J Elife (Cambridge). 2014 Jun 23:e02687. doi: 10.7554/eLife.02687. PMID:24957337[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Horiuchi H, Lippe R, McBride HM, Rubino M, Woodman P, Stenmark H, Rybin V, Wilm M, Ashman K, Mann M, Zerial M. A novel Rab5 GDP/GTP exchange factor complexed to Rabaptin-5 links nucleotide exchange to effector recruitment and function. Cell. 1997 Sep 19;90(6):1149-59. PMID:9323142
- ↑ Lippe R, Miaczynska M, Rybin V, Runge A, Zerial M. Functional synergy between Rab5 effector Rabaptin-5 and exchange factor Rabex-5 when physically associated in a complex. Mol Biol Cell. 2001 Jul;12(7):2219-28. PMID:11452015
- ↑ Delprato A, Merithew E, Lambright DG. Structure, exchange determinants, and family-wide rab specificity of the tandem helical bundle and Vps9 domains of Rabex-5. Cell. 2004 Sep 3;118(5):607-17. PMID:15339665 doi:10.1016/j.cell.2004.08.009
- ↑ Stenmark H, Vitale G, Ullrich O, Zerial M. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell. 1995 Nov 3;83(3):423-32. PMID:8521472
- ↑ Nagelkerken B, Van Anken E, Van Raak M, Gerez L, Mohrmann K, Van Uden N, Holthuizen J, Pelkmans L, Van Der Sluijs P. Rabaptin4, a novel effector of the small GTPase rab4a, is recruited to perinuclear recycling vesicles. Biochem J. 2000 Mar 15;346 Pt 3:593-601. PMID:10698684
- ↑ Lippe R, Miaczynska M, Rybin V, Runge A, Zerial M. Functional synergy between Rab5 effector Rabaptin-5 and exchange factor Rabex-5 when physically associated in a complex. Mol Biol Cell. 2001 Jul;12(7):2219-28. PMID:11452015
- ↑ Deneka M, Neeft M, Popa I, van Oort M, Sprong H, Oorschot V, Klumperman J, Schu P, van der Sluijs P. Rabaptin-5alpha/rabaptin-4 serves as a linker between rab4 and gamma(1)-adaptin in membrane recycling from endosomes. EMBO J. 2003 Jun 2;22(11):2645-57. PMID:12773381 doi:http://dx.doi.org/10.1093/emboj/cdg257
- ↑ Gauthier-Campbell C, Bredt DS, Murphy TH, El-Husseini Ael-D. Regulation of dendritic branching and filopodia formation in hippocampal neurons by specific acylated protein motifs. Mol Biol Cell. 2004 May;15(5):2205-17. Epub 2004 Feb 20. PMID:14978216 doi:10.1091/mbc.E03-07-0493
- ↑ Zhang Z, Zhang T, Wang S, Gong Z, Tang C, Chen J, Ding J. Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5. Elife (Cambridge). 2014 Jun 23:e02687. doi: 10.7554/eLife.02687. PMID:24957337 doi:http://dx.doi.org/10.7554/eLife.02687
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