Structural extension of the human exocyst is enabled by a minimal interface

Abstract

In multicellular organisms, the machinery responsible for polarized trafficking directs constitutive cargo secretion at distinct sites of the plasma membrane, cilia, and junctional structures. Central to this machinery is the exocyst complex, which tethers cargo vesicles to their destination membrane, alongside other intracellular membrane tethering roles. Precisely how the exocyst spatially integrates membranes and membrane resident binding partners is unclear. Here, we address the structural morphology and formation of the human exocyst complex. Through structural approaches coupled to predictive models, we determined that the exocyst and its subcomplexes have extended arm-like structures that help maximize its reach. Moreover, we demonstrate minimal intersubunit interaction, in contrast to prior models. Nucleation of the holocomplex occurs through a single site, explaining its spatial extension. Our results provide the biochemical basis for exocyst complex assembly, suggesting an ornate extended architecture. SignificanceCargo transport to the eukaryotic cell plasma membrane predominantly relies on the exocyst as a central, signal-integrating polarized trafficking complex. How this single cargo vesicle tethering complex can target diverse vesicles to destination membrane is poorly understood, partly due to inconsistent structural models. Here, we show an extended architecture of the human exocyst complex, revealing a minimal nucleation interface between its two subcomplexes. The distinct morphology of human exocyst, compared to yeast models, suggests a novel mechanism that supports its versatile role in membrane trafficking.