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

Taken together, the most straightforward interpretation of our results is as follows. The lumenal domains of individual p63 molecules interact to form noncovalently linked dimers, with the transmembrane domains possibly having an accessory role. These dimers would represent the basic unit from which higher oligomeric structures are built. Upon reaching their final destination, larger complexes form, requiring interactions of the cytoplasmic tails as well as the lumenal and transmembrane domains. The amino-terminal 23 residues of the cytoplasmic tails could either be directly involved in the interactions or, more likely, guarantee a conformation of the cytoplasmic tail that favors higher order assembly. The association of p63 into large complexes could prevent p63 molecules from entering budding vesicles and thereby provide a mechanism for retention. Alternatively, failure of the mutant p63 molecules to form the higher order complexes would result in leakage of the molecules out of the compartment with eventual delivery to the cell surface. This proposed model for the localization of p63 involves a retention rather than a retrieval mechanism, which is compatible with previous data suggesting that p63 is a stably anchored resident protein.