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Volume 272, Number 3, Issue of January 17, 1997 pp. 1970-1975
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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The Transmembrane Domain of a Carboxyl-terminal Anchored Protein Determines Localization to the Endoplasmic Reticulum

(Received for publication, September 16, 1996, and in revised form, November 7, 1996)

Mei Yang , Jan Ellenberg ^§ , Juan S. Bonifacino ^§ and Allan M. Weissman

From the  Laboratory of Immune Cell Biology, Division of Basic Sciences, National Cancer Institute and ^§ Cell Biology and Metabolism Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892

UBC6 is a C-terminal membrane-anchored (type IV) protein, native to Saccharomyces cerevisiae, where it is found in the endoplasmic reticulum. When expressed in mammalian cells, this novel ubiquitin-conjugating enzyme also localizes to the endoplasmic reticulum. UBC6 lacks a lumenal domain and contains no known endoplasmic reticulum retention signals. Analysis of chimeric proteins in which the cytosolic domain of UBC is linked to a heterologous transmembrane domain, or in which the UBC6 transmembrane domain is appended to an unrelated soluble protein, led to the determination that the transmembrane domain of UBC6 plays a dominant role in its compartmental localization. The basis for the transmembrane domain-mediated subcellular targeting of UBC6 was evaluated by lengthening the wild type UBC6 hydrophobic segment from 17 to 21 amino acids, which resulted in re-targeting to the Golgi complex. A further increase in length to 26 amino acids allowed this modified protein to traverse the secretory pathway and gain expression at the plasma membrane. These findings are consistent with models in which, in the absence of dominant cytosolic or lumenal targeting determinants, proteins may be sorted within the secretory pathway based on interactions between their transmembrane domains and the surrounding lipid bilayer.

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