Retention of p63 in an ER-Golgi intermediate compartment depends on the presence of all three of its domains and on its ability to form oligomers

The striking correlation between proper intracellular localization and Triton X-100-insolubility suggests a retention mechanism for p63 that involves homooligomerization. The model predicts that upon arrival at their final destination, p63 molecules encounter an environment that leads to self aggregation resulting in the formation of large oligomers. The specific conditions that might trigger the oligomerization of p63 are unknown, but could include differences in ion composition, lumenal pH or properties of the local membrane. This proposed retention mechanism is compatible with several additional findings. First, high levels of expression do not result in mislocalization of p63 to the plasma membrane, indicating that the p63 retention system is not saturable. If p63 interacted with a specific receptor, overexpression would likely lead to saturation of the retention machinery and the appearance of the protein at the cell surface. Second, as mentioned above, all three domains of p63 are necessary for complete retention, as would be expected if the molecule formed higher order structures. When Triton X-100-soluble p63 molecules were examined by sucrose gradient centrifugation or nonreducing SDS-PAGE, the majority of the molecules were present as noncovalently linked dimers (Schweizer et al., 1993a; Schweizer, A., J. Rohrer, and S. Kornfeld, unpublished data) . Interestingly, this dimerization of p63 is independent on the cytoplasmic tail, in contrast to the formation of higher oligomeric complexes.