Proteolytic Processing of the Extracellular Scaffolding Protein LEV-9 is Required for Clustering Acetylcholine Receptors [Neurobiology]

March 11th, 2014 by Briseno–Roa, L., Bessereau, J.–L.

Correct positioning of neurotransmitter-gated receptors at post-synapses is essential for synaptic transmission. At C. elegans neuromuscular junctions clustering of levamisole-sensitive acetylcholine receptors (L-AChRs) requires the muscle-secreted scaffolding protein LEV-9, a multidomain factor containing Complement Control Protein (CCP) modules. Here we show that LEV-9 needs to be cleaved at its C-terminus to exert its function. LEV-9 cleavage is not required for trafficking nor secretion but directly controls scaffolding activity. The cleavage site is evolutionarily conserved and post-translational cleavage ensures the structural and functional decoupling between different isoforms encoded by the lev-9 gene. Data mining indicates that most human CCP-containing factors are likely cleaved C-terminally from CCP tandems, suggesting that not only domain architectures but also cleavage location can be conserved in distant architecturally-related proteins.