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J. Biol. Chem., Vol. 276, Issue 50, 46975-46982, December 14, 2001
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From INSERM U.332 and Department of Cell Biology, Institut Cochin
de Génétique Moléculaire, 75014 Paris, France
The human immunodeficiency virus, type 1 (HIV-1)
entry process is triggered by interaction between the viral envelope
and a seven membrane-spanning domain receptor at the cell surface, usually the CCR5 chemokine receptor. Different naturally occurring mutations in the CCR5 gene abolish receptor function, the
most frequent being a 32-nucleotide deletion resulting in a truncated protein (
Determinants of the trans-Dominant Negative Effect of
Truncated Forms of the CCR5 Chemokine Receptor*
32) lacking the last three transmembrane domains (TM5-7). This mutant is retained in the endoplasmic reticulum and exerts a
trans-dominant negative (TDN) effect on the wild type,
preventing its exit from this compartment. This TDN effect is often
considered as evidence for the oligomerization of CCR5 during transport
to the cell surface. Here we use a genetic approach to define the structural determinants of the TDN effect of the 32 mutant. It was
abolished by certain deletions and by mutations of cysteine residues
preventing formation of a disulfide link between the first and second
extracellular loops, suggesting that conformation of 32 is important
for its interaction with CCR5. To circumvent this problem, we used
chimeric forms of the 32 and wild type CCR5, consisting in
substitutions with homologous domains from the mouse CCR5. All chimeric
full-length receptors were expressed at the cell surface and were
functional for interaction with HIV-1 or with a chemokine ligand, when
assayed. The TDN effect was only observed if both the TM3 domain in
CCR5 and the TM4 domain in 32 were from human origin, whereas the
rest of the proteins could be from either origin. This suggests that
the TDN effect involves some form of interaction between these
transmembrane domains. Alternatively, but less likely to us,
substitutions in TM4 could affect the conformation of CCR5 in the
endoplasmic reticulum but not at the cell surface. However that may be,
it seems that the TDN effect of the 32 mutant has no bearing to the
issue of CCR5 dimerization and to its possible role in the processing
of the receptor to the cell surface.
*
This work was supported by the Agence Nationale de Recherche
sur le SIDA.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correpondence should be addressed: Inst. Cochin de
Génétique Moléculaire, 22 rue Méchain,
75014 Paris, France. E-mail: alizon@cochin.inserm.fr.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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