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MBC in Press, published online ahead of print August 15, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0100

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Submitted on February 5, 2007
Revised on July 12, 2007
Accepted on August 2, 2007

Rabaptin-5-independent Membrane Targeting and Rab5 Activation by Rabex-5 in the Cell

Huaiping Zhu,* Guangyu Zhu,{dagger} Jay Liu,* Zhimin Liang,* Xuejun C. Zhang,{dagger} and Guangpu Li*

*Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; {dagger}Crystallography Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

Monitoring Editor: Patrick Brennwald

Rabex-5 is a guanine nucleotide exchange factor (GEF) for Rab5. Here we report the identification of a novel functional domain of Rabex-5 that is essential for its membrane targeting and Rab5 GEF activity in vivo. The data show that full-length Rabex-5 efficiently activates Rab5 in the cell. However, the GEF domain itself (residues 135–399) is inactive in this respect, despite its activity in vitro. Generation and characterization of a series of Rabex-5 constructs reveal that the GEF domain is unable to target to early endosomes and a sequence N-terminal to the GEF domain can restore its early endosomal targeting and its ability to activate Rab5 in the cell. This region (residues 81–135) is termed membrane-binding motif (MBM), which together with the downstream helical bundle domain (residues 135–230) forms an early endosomal targeting (EET) domain necessary and sufficient for association with early endosomes. Furthermore, several active Rabex-5 constructs do not contain the Rabaptin-5-binding domain in the C-terminal region. Thus Rabex-5 can target to early endosomes via the EET domain and activate Rab5 in a Rabaptin-5-independent manner in vivo. We discuss a model to reconcile these in vivo data with previous in vitro results on Rabex-5 function and its interaction with Rabaptin-5.

Address correspondence to: Guangpu Li (guangpu-li{at}ouhsc.edu)




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