Rab5 is a small GTPase that regulates early endosome fusion. We present here the crystal structure of the Rab5 GTPase domain in complex with a GTP analog and the C-terminal domain of effector Rabaptin5. The proteins form a dyad-symmetric Rab5−Rabaptin52−Rab5 ternary complex with a parallel coiled-coil Rabaptin5 homodimer in the middle. Two Rab5 molecules bind independently to the Rabaptin5 dimer using their switch and interswitch regions. The binding does not involve the Rab complementarity-determining regions. We also present the crystal structures of two distinct forms of GDP−Rab5 complexes, both of which are incompatible with Rabaptin5 binding. One has a dislocated and disordered switch I but a virtually intact switch II, whereas the other has its -sheet and both switch regions reorganized. Biochemical and functional analyses show that the crystallographically observed Rab5−Rabaptin5 complex also exists in solution, and disruption of this complex by mutation abrogates endosome fusion.
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-sheet and both switch regions reorganized. Biochemical and functional analyses show that the crystallographically observed Rab5−Rabaptin5 complex also exists in solution, and disruption of this complex by mutation abrogates endosome fusion.
