Hypothetical model for function of munc13-4 and rab27. Activation of cells targets munc13-4 and rab27 to each other's vicinity, establishing a specific domain on secretory lysosomes. Colocalization facilitates the interaction between the 2 proteins and, because rab27 and munc13-4 have independent membrane-binding determinants, their interaction enhances the affinity of the complex for the secretory lysosome membrane. At this point, the interaction with rab27 could fold munc13-4 in a conformation that allows the first C2 domain to bridge the apposing bilayers of secretory lysosome and plasma membrane.⁵⁰  The complex can now serve as nucleation point or coincidence detection unit for interaction with other proteins important for secretory lysosome release. The C-terminal part of munc13-4 might bind to syntaxin-11 or engage Doc2α, which then interacts with SNAP-23, establishing a regulatory circuit for controlling a cognate SNARE complex for fusion with the plasma membrane. The interaction with rab27-GTP secures the recruitment of slp2 and other effectors involved in tethering the secretory lysosome to the plasma membrane. Loss of rab27 binding uncouples these events and interferes with degranulation.