4n3z

From Proteopedia

Crystal structure of Rabex-5delta and Rabaptin-5C21 complex

Structural highlights

4n3z is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.1Å
Ligands:
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]

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^[4]

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
↑ 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