Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex.

[10] Both Vps26 and arrestins are composed of two structurally related β-sheet domains forming extensive interfaces with each other, using polar and electrostatic contacts to create interdomain interactions for ligand binding.

Vps26 protein has extended C-terminal tails that do not contain identifiable clathrin- or AP2-binding sequences, and therefore cannot form stable intramolecular contacts with clathrin and AP2, which has been observed for arrestins.

Vps26B contains several putative serine phosphorylation residues within this disordered tail, which may represent a potential mechanism to modulate the difference between Vps26A and Vps26B.

A recent study conducted by Bugarcic et al. pinpointed that this disordered tail on C-terminal region of Vps26B is one of the underlying factors that contributes to the failure for Vps26B-containing Retromer to associate with CI-M6PR, ultimately leading to CI-M6PR degradation, accompanied with increased cathepsin D secretion.