The association of the Vps35-Vps29-Vps26 complex with the cytosolic domains of cargo molecules on endosomal membranes initiates the activation of retrograde trafficking and cargo capture. The nucleation complex is formed through the interaction of VPS complex with GTP-activated Rab7 with clathrin, clathrin-adaptors and various binding proteins.
The SNX-BAR dimer enters the nucleation complex via direct binding or lateral movement on endosomal surface. The increased level of Retromer SNX-BARs causes a conformational switch to a curvature-inducing mode which initiates membrane tubule formation. Once the cargo carriers are matured, the carrier scission is then catalyzed by dynamin-II or EHD1, together with the mechanical forces generated by actin polymerization and motor activity.
The cargo carrier is transported to the TGN by motor proteins such as dynein. Tethering of the cargo carrier to the recipient compartment is thought to lead to the uncoating of the carrier, which is driven by ATP-hydrolysis and Rab7-GTP hydrolysis. Once released from the carrier, the Vps35-Vps29-Vps26 complex and the SNX-BAR dimers get recycled back onto the endosomal membranes.