Rab5 complex with Rabaptin5 C-terminal Domain
Homo sapiens (human)
G protein is a signal transmitter which contains a guanine nucleotide and transits between active (GTP bound) and inactive (GDP bound) state. While almost all G proteins exist as GDP bound form in the stationary state, a specific stimulus increases the amount of the GTP bound form and then transmits the signal downstream. G protein families are largely divided into two groups; heterotrimeric G proteins, which couple with 7-helix transmembrane penetrating receptor, and monomeric small G proteins. Rab proteins, which belong to monomeric small G proteins, regulate membrane traffic. Rab5 is an essential regulator of endocytosis and mediates early endosome fusion in concert with the SNARE complex and other proteins. To perform accurate signal transmission, proteins must be localized at the proper position in the cell. Linker proteins which have several protein binding domains regulate the localization of the signal transmitters. Rabaptin5, a type of linker protein, gathers proteins which are related in membrane traffic. Especially, Rabaptin5 binds to GTP-bound Rab5 with its C terminal region. This interaction enables GTP-bound Rab5 to be localized on the cytoplasmic side of early endosome or endocytic vesicles. While in the GDP-bound state, Rab5 becomes cytosolic and associates with GDP-dissociation inhibitor (GDI).
Zhu et al. reported the crystal structure of GDP-bound Rab5, GTP-bound Rab5 and Rab5-Rabaptin5 complex. These results suggested a molecular mechanism which regulates the localization of Rab5. Rab5 contains a central 6-strand beta-sheet flanked by 5 alpha-helices. The structure of the GDP-bound form and the GTP-bound form are different around the switch 1 and switch 2 regions. Switch 2 and the domain between switch 1 and switch 2 (interswitch domain) of the GTP-bound form interact with the C terminal region of Rabaptin5 but the GDP-bound form cannot bind to Rabaptin5. Zhu et al. divided GDP-bound Rab5 into two groups (form A and form B) with the point of the structure of switch 1 and switch 2. The structures of switch 1 and switch 2 in form A are largely different from those of the GTP-bound form, especially, switch 1 of form A has an extra beta-sheet between the second and third beta-sheet. In form B, the structure of switch 2 is almost similar to that of the GTP-bound form, while the structure of switch 1 is different from that of the GTP-bound form. The physiological difference of form A and form B in GDP-bound Rab5 is unclear, however, it is suggested that form A and form B coexist in the cell and switch 2 of form A interacts with GDI which is in the cytosol, that may promote the cytosolic localization of GDP bound Rab5. Zhu et al. reported that two GTP-bound Rab5s and two C terminal domain of Rabaptin5s formed tetrameric complex in the crystal, Rab5-Rabaptin5-Rabaptin5-Rab5. They suggested that the complex would become dyad-symmetric, Rab5-Rabaptin5-Rabaptin5-Rab5 under physiological conditions.
Protein Data Bank (PDB)
Zhu, G. Zhai, P. Liu, J. Terzyan, S. Li, G. Zhang, X.C.; "Structural basis of Rab5-Rabaptin5 interaction in endocytosis"; Nat.Struct.Mol.Biol.; (2004) 11:975-983 PubMed:15378032.
author: Daisuke Ino