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MBC in Press, published online ahead of print June 13, 2003
Mol. Biol. Cell 10.1091/mbc.E03-03-0192

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Submitted on March 31, 2003
Revised on April 23, 2003
Accepted on May 12, 2003

Dislocation of a type I membrane protein requires interactions between membrane-spanning segments within the lipid bilayer

Brendan N. Lilley1, Domenico Tortorella1, and Hidde L. Ploegh1*

1 Department of Pathology, Harvard Medical School, Boston, MA 02115

* Corresponding author. E-mail address: ploegh{at}hms.harvard.edu.

The human cytomegalovirus gene product US11 causes rapid degradation of class I major histocompatibility complex (MHCI) heavy chains by inducing their dislocation from the endoplasmic reticulum (ER) and subsequent degradation by the proteasome. This set of reactions resembles the endogenous cellular quality control pathway that removes misfolded or unassembled proteins from the ER. We show that the transmembrane domain (TMD) of US11 is essential for MHCI heavy chain dislocation, but dispensable for MHCI binding. A Gln residue at position 192 in the US11 TMD is crucial for the ubiquitination and degradation of MHCI heavy chains. Cells that express US11 TMD mutants allow formation of MHCI-{beta}2m complexes, but their rate of egress from the ER is significantly impaired. Further mutagenesis data are consistent with the presence of an alpha-helical structure in the US11 TMD essential for MHCI heavy chain dislocation. The failure of US11 TMD mutants to catalyze dislocation is a unique instance in which a polar residue in the TMD of a type I membrane protein is required for that protein's function. Targeting of MHCI heavy chains for dislocation by US11 thus requires the formation of interhelical hydrogen bonds within the ER membrane.




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