Siebert, M., Böhme, M.A., Driller, J.H., Babikir, H., Mampell, M.M., Rey, U., Ramesh, N., Matkovic, T., Holton, N., Reddy-Alla, S., Göttfert, F., Kamin, D., Quentin, C., Klinedinst, S., Andlauer, T.F., Hell, S.W., Collins, C.A., Wahl, M.C., Loll, B., Sigrist, S.J. (2015). A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones.  eLife 4(): e06935.

FBrf0229297

Research paper

Synaptic vesicles (SVs) fuse at active zones (AZs) covered by a protein scaffold, at Drosophila synapses comprised of ELKS family member Bruchpilot (BRP) and RIM-binding protein (RBP). We here demonstrate axonal co-transport of BRP and RBP using intravital live imaging, with both proteins co-accumulating in axonal aggregates of several transport mutants. RBP, via its C-terminal Src-homology 3 (SH3) domains, binds Aplip1/JIP1, a transport adaptor involved in kinesin-dependent SV transport. We show in atomic detail that RBP C-terminal SH3 domains bind a proline-rich (PxxP) motif of Aplip1/JIP1 with submicromolar affinity. Pointmutating this PxxP motif provoked formation of ectopic AZ-like structures at axonal membranes. Direct interactions between AZ proteins and transport adaptors seem to provide complex avidity and shield synaptic interaction surfaces of pre-assembled scaffold protein transport complexes, thus, favouring physiological synaptic AZ assembly over premature assembly at axonal membranes.

PMC4536467 (PMC) (EuropePMC)