Rep15 interacts with several Rab GTPases and has a distinct fold for a Rab effector

In their GTP-bound (active) form, Rab proteins interact with effector proteins that control downstream signaling. One such Rab15 effector is Rep15, which is known to have a role in receptor recycling from the endocytic recycling compartment but otherwise remains poorly characterized. Here, we report the characterization of the Rep15:Rab15 interaction and identification of Rab3 paralogs and Rab34 as Rep15 interacting partners from a yeast two-hybrid assay. Biochemical validation of the interactions is presented and crystal structures of the Rep15:Rab3B and Rep15:Rab3C complexes provide additional mechanistic insight. We find that Rep15 adopts a globular structure that is distinct from other reported Rab15, Rab3 and Rab34 effectors. Structure-based mutagenesis experiments explain the Rep15:Rab interaction specificity. Rep15 depletion in U138MG glioblastoma cells impairs cell proliferation, cell migration and receptor recycling, underscoring the need for further clarification of the role of Rep15 in cancer. Rep15 is an effector that interacts with the GTPase Rab15. Here, the authors show that Rep15 also interacts with Rab3 paralogs and Rab34, present crystal structures of Rep15:Rab complexes and find that Rep15 depletion in glioblastoma cells decreases proliferation and mobility.

Automated summary

Rep15 is an effector that interacts with the GTPase Rab15. Here, the authors show that Rep15 also interacts with Rab3 paralogs and Rab34, present crystal structures of Rep15:Rab complexes and find that Rep15 depletion in glioblastoma cells decreases proliferation and mobility.