Models for exocyst activation mechanisms. (A) Model for dual exocyst-activation mechanism at the bud tip. During recruitment to the bud tip (red circle), the exocyst remains in a basal, autoinhibited state. While tethering a secretory vesicle to the plasma membrane (red square), the exocyst is activated by two of its binding partners. Each of the partners is color-coded to match to the subunit with which they interact. Sro7 interacts with Exo84 through its N-terminus (pink arrow) resulting in an increased binding of the exocyst for Sec4-GTP through the Sec15 subunit (red arrow). The first 168 aa of Exo84 do not appear in the CryoEM or negative stain EM electron density, likely due to flexibility/dynamics, and are depicted by a pink line. We previously reported that Rho GTPases on the plasma membrane also activate the exocyst by interacting with Exo70 (blue arrow) resulting in an increased binding affinity of the exocyst for Snc2 through the Sec6 subunit (purple arrow) and that these changes were associated with corresponding movement of Exo70 and opening up of Sec6. In the red square Sro7 is depicted as a homo-oligomer interacting with and tethering vesicles through its own interactions with Sec4-GTP. Sro7-tethered vesicle clusters primed at the site of exocytosis are shown in the yeast bud tip (shown on left) as vesicles with pink (Sro7 oligomer) lines connecting them. Putative allosteric changes associated with Sro7- or Rho-binding are modeled using the exocyst CryoEM structure (PDB accession no. 5YFP) and the Exo70 gain-of-function negative stain EM structure (PDB accession no. 6VKL). (B) Speculative Model for structurally related exocyst activation mechanisms shared between yeasts and animal cells through the Exo84 subunit resulting in increased avidity of the complex for Rab GTPase on the vesicle.