Fig. 4. Proposed model of basal PLCε regulation at the perinuclear membrane.

(Left) PLCε is present predominantly in the cytoplasm, and is maintained in a low-activity state by the autoinhibitory X–Y linker (hot pink) and the C2-RA1 linker (purple). The CDC25, PH, and RA2 domains, along with EF1/2, are not essential for full basal activity and may be flexibly connected to, or only transiently interact with, the PLCε core^18,22,32,33. (Right) Localization of PLCε to the perinuclear membrane through interactions between the RA1 domain and the scaffolding protein mAKAP increase lipase activity^17,19. RA1 binding to mAKAP could alter the conformation of, or displace, the C2-RA1 linker, increasing basal activity. Membrane association would also increase basal activity via interfacial activation¹², which may be facilitated by interactions between the α_X–Y helix and the membrane or, alternatively, with other domains in PLCε or proteins at the target membrane, such as activated Rap1A.