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Molecular basis of the activation of the Rabex‐5 GEF activity by Rabaptin‐5 in endocytosis (802.27)
Author(s) -
Zhang Zhe,
Zhang Tianlong,
Yu Fang,
Chen Jiangye,
Ding Jianping
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.802.27
Subject(s) - medicine , biophysics , biology
Rabex‐5 and Rabaptin‐5 function together to activate small GTPase 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‐5CC, the Rabex‐5CC‐Rabaptin‐5C21 2 complex, and the Rabex‐5Δ‐Rabaptin‐5C21 2 complex. Our structural and biological data together show that Rabex‐5CC assumes an amphipathic α‐helix which may bind weakly to a nonpolar surface groove of the GEF domain to occlude the substrate‐binding site, resulting in autoinhibition. The linker between the GEF and CC domains plays a role in the autoinhibition probably by modulating the relative conformation of the two domains. Binding of Rabaptin‐5C21 2 to Rabex‐5 displaces Rabex‐5CC, yielding a largely exposed substrate‐binding site and thus releasing the GEF activity. These results reveal the molecular mechanism of the regulation of the Rabex‐5 GEF activity. Grant Funding Source : Supported by grants from the National Natural Science Foundation of China (31230017 and 31000327)