Journal of Virology, April 2000, p. 3273-3283, Vol. 74, No. 7
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Chain Contains Two
Homologous Domains with Which Simian Immunodeficiency Virus Nef
Interacts and Mediates Down-Modulation
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
Received 10 September 1999/Accepted 13 December 1999
We have recently demonstrated that simian immunodeficiency virus
(SIV) Nef binds to the
chain of the T-cell receptor (TCR), leading
to its down-modulation from T-cell surfaces (I. Bell, C. Ashman, J. Maughan, E. Hooker, F. Cook, and T. A. Reinhart, J. Gen.
Virol. 79:2717-2727, 1998). Using a panel of human as well as rhesus
macaque TCR
cytoplasmic domain mutants, we have identified in this
report two linear peptides in the cytoplasmic domain of TCR
which
independently interact with SIV Nef. Each SIV Nef interaction domain
was sufficient in the absence of the other for interaction with SIV Nef
in a yeast two-hybrid assay. In parallel, we demonstrated that Nef
down-modulation of CD8-TCR
fusion proteins containing full-length
or truncated portions of the TCR
cytoplasmic domain occurs in
transiently transfected 293T cells. Furthermore, using proteins
expressed in Escherichia coli, a glutathione
S-transferase-Nef fusion protein coprecipitated histidine-tagged portions of the TCR
cytoplasmic domain which contained SNID-1 or SNID-2. The peptides targeted by SIV Nef, YNELNL
and YSEIGMKGERRR, are portions of the first and second of three
immunoreceptor tyrosine-based activation motifs which are important in
signal transduction, thymocyte development, and TCR biogenesis. These
results demonstrate that SIV Nef binds to two distinct domains on TCR
in the absence of other T-cell-specific factors, and that
interaction with either domain is sufficient to cause down-modulation
of TCR
.
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