A role for the syntaxin N-terminus

Intracellular membrane fusion steps in eukaryotes require the syntaxin family of SNARE (soluble <i>N</i>-ethylmaleimide-sensitive fusion protein-attachment protein receptor) proteins. Syntaxins are regulated at several levels through interactions with regulatory proteins, including the SM (Sec1p/Munc18) proteins. Key to understanding this regulation is the characterization of different SM-syntaxin binding interactions at the molecular level and in terms of their contribution to function <i>in vivo</i>. The most conserved SM-syntaxin binding mode is through interaction of the syntaxin's extreme N-terminal peptide with a hydrophobic pocket on the surface of the SM protein. Surprisingly, mutant versions of two different SM proteins abrogated for this binding display no discernable phenotypes <i>in vivo</i>. In this issue of the Biochemical Journal , Johnson et al. demonstrate that loss of the N-terminal binding interaction between the syntaxin UNC-64 and the SM protein UNC-18 severely impairs neuromuscular synaptic transmission in <i>Caenorhabditis elegans</i>, resulting in an unco-ordinated phenotype. In contrast, loss of a second mode of SM-syntaxin binding has no detectable effect. Collectively, these results suggest that, although different membrane trafficking steps are all regulated by SM-syntaxin interactions using similar binding modes, they are differentially regulated, highlighting the need for careful dissection of the binding modes