The active zone component RIM (Rab3 interacting molecule) is implicated in the regulation of synaptic vesicle release and synaptic plasticity (Wang et al., 1997, Castillo et al., 2002). RIM homologs contain distinct domains, which mediate interactions with partner proteins. RIM thus contributes to assemble and modulate pivotal synaptic components including calcium channels, the small GTPase Rab3 and Munc13 at the active zone. The C2A domain of human RIM has been previously identified to harbour a missense mutation in patients with autosomal dominant cone-rod dystrophy (CORD7), a clinical syndrome hallmarked by retinal degeneration and enhanced cognitive abilities (Sisodiya et al., 2007). To understand whether these peculiar effects are associated with synaptic dysfunction and how the structure of the C2A domain figures in this process, we have employed Drosophila melanogaster, which possesses a single RIM homolog (Graf et al, 2012; Müller et al., 2012). Crystallographic analysis of the C2A domain of fly RIM revealed compelling similarity between Drosophila and rat RIM homologs (Dai et al., 2005). The structural conservation extended to a doublet of arginine residues at the bottom of the domain, which may function as a putative interaction interface and which is affected by the CORD7 mutation. To functionally probe this protein site we have engineered two RIM mutant transgenes possibly affected by the CORD7 mutation (R915H and R916H). Future studies will assess the functional consequences of these changes on synaptic transmission.
References
Castillo P.E., Schoch S., Schmitz F., Südhof T.C., Malenka R.C. (2002) RIM1alpha is required for presynaptic long-term potentiation. Nature 415:327-30
Dai H, Tomchick DR, García J, Südhof TC, Machius M, Rizo J. (2005) Crystal structure of the RIM2 C2A-domain at 1.4 A resolution. Biochemistry. 44:13533-42.
Graf ER, Valakh V, Wright CM, Wu C, Liu Z, Zhang YQ, DiAntonio A (2012) RIM Promotes Calcium Channel Accumulation at Active Zones of the Drosophila Neuromuscular Junction. Journal of Neuroscience 32:16586-16596.
Müller M, Liu KSY, Sigrist SJ, Davis GW (2012) RIM Controls Homeostatic Plasticity through Modulation of the Readily-Releasable Vesicle Pool. Journal of Neuroscience 32:16574-16585.
Sisodiya S.M., Thompson P.J., Need A., Harris S.E., Weale M.E., Wilkie S.E., Michaelides M., Free S.L., Walley N., Gumbs C., Gerrelli D., Ruddle P., Whalley L.J., Starr J.M., Hunt D.M., Goldstein D.B., Deary I.J., Moore A.T. (2007) Genetic enhancement of cognition in a kindred with cone-rod dystrophy due to RIMS1 mutation. J. Med. Genet. 44:373-80
Wang Y., Okamoto M., Schmitz F., Hofmann K., Südhof T.C. (1997) Rim is a putative Rab3 effector in regulating synaptic vesicle fusion. Nature 388:593-8
Supported by DFG grants to TL (LA 2861/1-1) and MH (HE 2621/4-2 & SFB 581 TP B27)