| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Receptor 2
*
Departments of Antibody Technology, Molecular Oncology, and Protein Engineering, Genentech Inc., South San Francisco, CA 94080; and
Department of Surgery, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121
The human IFN-
receptor (hIFNAR) is a complex composed of at
least two chains, hIFNAR1 and hIFNAR2. We have performed a
structure-function analysis of hIFNAR2 extracellular domain regions
using anti-hIFNAR2 mAbs (1D3, 1F3, and 3B7) and several type I
human IFNs. These mAbs block receptor activation, as determined by
IFN-stimulated gene factor 3 formation, and block the antiviral
cytopathic effects induced by type I IFNs. We generated alanine
substitution mutants of hIFNAR2-IgG and determined that regions of
hIFNAR2 are important for the binding of these blocking mAbs and
hIFN-2/1. We further demonstrated that residues E78, W101, I104,
and D105 are crucial for the binding of hIFN-2/1 and form a
defined protrusion when these residues are mapped upon a structural
model of hIFNAR2. To confirm that residues important for ligand binding
are indeed important for IFN signal transduction, we determined the
ability of mouse L929 cells expressing hIFNAR2 extracellular domain
mutants to mediate hIFN signal. hIFN-8, previously shown to signal a
response in L929 cells expressing hIFNAR1, was unable to signal in L929
cells expressing hIFNAR2. Transfected cells expressing hIFNAR2
containing mutations at residues E78, W101, I104, or D105 were
unresponsive to hIFN-2, but remained responsive to hIFN-ß. In
summary, we have identified specific residues of hIFNAR2 important for
the binding to hIFN-2/1 and demonstrate that specific regions of the
IFNAR interact with the subspecies of type I IFN in different
manners.
This article has been cited by other articles:
|
|
 |
|
  S. R. Quadt-Akabayov, J. H. Chill, R. Levy, N. Kessler, and J. Anglister Determination of the human type I interferon receptor binding site on human interferon-{alpha}2 by cross saturation and an NMR-based model of the complex Protein Sci., November 1, 2006; 15(11): 2656 - 2668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. S. Cull, P. A. Tilbrook, E. J. Bartlett, N. L. Brekalo, and C. M. James Type I interferon differential therapy for erythroleukemia: specificity of STAT activation Blood, April 1, 2003; 101(7): 2727 - 2735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Roisman, J. Piehler, J.-Y. Trosset, H. A. Scheraga, and G. Schreiber Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking PNAS, November 6, 2001; 98(23): 13231 - 13236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Barthe, F.-X. Mahon, M.-J. Gharbi, C. Faberes, C. Bilhou-Nabera, A. Hochhaus, J. Reiffers, and G. Marit Expression of interferon-{alpha} (IFN-{alpha}) receptor 2c at diagnosis is associated with cytogenetic response in IFN-{alpha}-treated chronic myeloid leukemia Blood, June 1, 2001; 97(11): 3568 - 3573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chuntharapai, K. Dodge, K. Grimmer, K. Schroeder, S. A. Marsters, H. Koeppen, A. Ashkenazi, and K. J. Kim Isotype-Dependent Inhibition of Tumor Growth In Vivo by Monoclonal Antibodies to Death Receptor 4 J. Immunol., April 15, 2001; 166(8): 4891 - 4898. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
