Endoplasmic reticulum localization of Sec12p is achieved by two mechanisms: Rer1p-dependent retrieval that requires the transmembrane domain and Rer1p-independent retention that involves the cytoplasmic domain

On the other hand, the structural requirement of the TMD remains to be clarified as discussed above. While the Sec12p TMD accepts rather extensive alterations, a distri-bution of the hydrophobicity with the central core may be the feature of the signal. Rerlp is an important player in this retrieval process. Is it possible that this molecule recognizes a variety of TMD signals as a receptor? Since Rerlp is an integral membrane protein with four membrane spans, there is a chance that such transmembrane regions physically interact with the Secl2p TMD. Such a possibility is testable by biochemical means and is now being investigated. Rerlp has highly charged regions in both the termini and the middle of the molecule. Such structural properties of Rerlp might have some relation to the hydrophobicity gradient in the TMD signal.