Many kinds of endosomes exist in cells that organise transport. Cargoes move from one kind to another as part of their itinerary. How do they do it so efficiently? Our latest #preprint is out detailing how very early endosomes mature in a robust manner.

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Thanks to @MonashBDI and @EMBLAustralia for the home. Shoutout to @NerdyCammy for running such a great imaging centre @MIPS_Australia where we did all the FLIM - you rock!.

This was an excellent interdisciplinary collaborative work between @cellphylab, headed by Senthil Arumugam, and the Iyer-Biswas lab @sfiscience with great contributions from Kunaal and Charlie on the simulations & analysis fronts!.

In summary, the maturation of newly formed very early endosomes (APPL1+ve) occurs through a ‘trigger and convert’ mechanism via N-terminal of EEA1 binding following interaction with mature early endosomes with C-terminally bound EEA1 extending the N-terminal into the cytosol

Turning to Monte Carlo simulations we captured the triggering by N-terminal binding and showed that heterotypic collisions and clustering of EEA1 result in overcoming the intrinsic randomness of the system and underpin the deterministic maturation of very early endosomes.

Using live FLIM we could see that EEA1 triggers conversion through N-terminal binding to the endosome, before swapping to C-terminal binding following lipid conversion. Also, endosomal fusion was dependent on at least one of the endosomes being a C-terminally bound EEA1 one.

Which end binds first? Is there a precedence in N- vs C-terminal binding? We used FLIM-FRET to investigate the orientation of EEA1 on the newly forming as well as pre-existing endosomes. We found two distinct populations!

Heterotypic collisions proceed immediate endosomal maturation! We observed many kinds of heterotypic interactions that resulted in conversion. How do these physical interactions result in maturation? The multivalent binding of EEA1 to endosomes at both ends holds the answer!