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APPL (Adaptor protein containing PH domain, PTB domain and leucine zipper motif) is an adaptor protein with two isoforms APPL1 and APPL2. As a scaffold protein, the interaction of APPL with Akt2 [1], small GTPases [2], FSHR, and AdipoR [3] are associated with the roles in cell proliferation, cell cycle control, metabolism/insulin sensing [4], [5], relaying signal from endosome and transcription by activating AMPK related signaling pathway [6]. As a protein communication hub, APPL provdes a mechanism for spatial regulation of signaling transmission and processing. However, it has also been shown that APPL2 plays opposing functions from APPL1 and there have been emerging evidences that BAR-PH domain of APPL1 and APPL2 can interact with each other to form heterodimer in vivo. The structure of APPL2 BAR-PH domain has been solved to resolution of 3.2 Å using X-ray crystallography. The dimer exhibits a canonical four-helical fold of conformation, just like the shape of crescent or banana, which is implicated in the assocication with curved membranes. The difference between APPL1 BP domain and APPL2 BP domain lays in the curvature of the crescents. The curvature radius increases to ~70 Å, in sharp contrast with ~55 Å of APPL1 BP dimer’s [7]. It has been proposed that curvature radius of BAR family protein corresponds to specific type of endosome to which it binds. Also, the protein surface shows different electrostatic property. Thus it is reasonable to conclude that the structure of APPL2 BAR-PH domain may be implicated in alteration of endosome assocation specificity, also in the change of the profile of spatial regulation of signaling transmission.

The crystal structure of APPL2 BAR-PH domain