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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.

The T-Cell Receptor zeta  Chain Contains Two Homologous Domains with Which Simian Immunodeficiency Virus Nef Interacts and Mediates Down-Modulation

Todd M Schaefer, Ian Bell, Beth A. Fallert, and Todd A. Reinhart*

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 zeta  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 zeta  cytoplasmic domain mutants, we have identified in this report two linear peptides in the cytoplasmic domain of TCR zeta  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 zeta  fusion proteins containing full-length or truncated portions of the TCR zeta  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 zeta  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 zeta  in the absence of other T-cell-specific factors, and that interaction with either domain is sufficient to cause down-modulation of TCR zeta .

* Corresponding author. Mailing address: Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, 130 DeSoto St., Pittsburgh, PA 15261. Phone: (412) 648-2341. Fax: (412) 383-8926. E-mail: REINHAR+{at}pitt.edu.

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.


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