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Receptor 2 Α the Human IFN- Ligand Binding and Signal Transmission In Determination of Residues Involved in Ligand Binding and Signal Transmission in the Human IFN-α Receptor 2 This information is current as A. Chuntharapai, V. Gibbs, J. Lu, A. Ow, S. Marsters, A. of September 24, 2021. Ashkenazi, A. De Vos and K. Jin Kim J Immunol 1999; 163:766-773; ; http://www.jimmunol.org/content/163/2/766 Downloaded from References This article cites 34 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/163/2/766.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 24, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1999 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Determination of Residues Involved in Ligand Binding and Signal Transmission in the Human IFN-a Receptor 2 A. Chuntharapai,* V. Gibbs,† J. Lu,* A. Ow,† S. Marsters,* A. Ashkenazi,* A. De Vos,* and K. Jin Kim1* The human IFN-a 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-a2/a1. We further dem- onstrated that residues E78, W101, I104, and D105 are crucial for the binding of hIFN-a2/a1 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 Downloaded from important for IFN signal transduction, we determined the ability of mouse L929 cells expressing hIFNAR2 extracellular domain mutants to mediate hIFN signal. hIFN-a8, 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-a2, but remained responsive to hIFN-b. In summary, we have identified specific residues of hIFNAR2 important for the binding to hIFN-a2/1 and demonstrate that specific regions of the IFNAR interact with the subspecies of type I IFN in different manners. The Journal of Immunology, 1999, 163: 766–773. http://www.jimmunol.org/ ype I IFNs are a family of cytokines defined by their there may be additional species-specific components required for antiviral activities. Human IFNs include at least 14 sub- the antiproliferative response (12). Recently, Petricoin et al. (13) T species of hIFN-a,2 one hIFN-b, one hIFN-v, and one reported that the antiproliferative action, but not the antiviral ac- hIFN-t (1, 2). These type I hIFNs share a common receptor (IF- tion or the activation of the JAK-STAT pathway, of IFN-a re- NAR) (3, 4), which is composed of two chains, a 135-kDa a sub- quires TCR signaling components. unit (hIFNAR1) (5) and a 115-kDa b subunit (hIFNAR2) (6, 7). hIFNAR2 is a 515-aa protein composed of an ECD of 217 res- Three different forms of hIFNAR2 have been reported: a 40-kDa idues. The ECD of hIFNAR2 is composed of two domains (;100 soluble form designated hIFNAR2a (6), a 55-kDa short form residues/domain), domain 1 and domain 2. IFN-mediated signaling by guest on September 24, 2021 known as hIFNAR2b (6), and a 115-kDa long form known as is initiated by ligand-induced receptor dimerization via the ECD, hIFNAR2c (7). These three forms are derived by alternative splic- tyrosine phosphorylation of the Tyk2 and Jak1 tyrosine kinases, ing of the same gene. Only hIFNAR2c mediates a biological re- and subsequent phosphorylation of the Stat1 and Stat2 proteins. sponse when associated with hIFNAR1 (5) and is the form of the Activated STATs translocate to the nucleus as an IFN-stimulated receptor we have utilized in this study. response element 3 (ISGF3) complex and induce the transcription When hIFNAR1 is expressed alone in mouse cells, there is no of IFN-stimulated genes (13). There are multiple IFNs in the type significant IFN-a binding; however, the expression of hIFNAR2 I IFN family that initiate receptor dimerization. To understand how alone produces a low affinity ligand-binding receptor (0.5–1 nM). the same receptor interacts with these different IFN subtypes, in this The coexpression of hIFNAR1 and hIFNAR2 results in a high study we have investigated the interaction of type I IFNs with hIF- affinity receptor complex (10–100 pM) (8–10). These results dem- NAR2 using soluble hIFNAR2-IgG immunoadhesin and blocking onstrate that hIFNAR2 is the ligand-binding subunit, but hIFNAR1 mAbs. Using alanine-scanning mutagenesis, we have determined res- contributes to the formation of a high affinity receptor. It has been idues on hIFNAR2 that are important for type I IFN binding. We have shown that the coexpression of hIFNAR1 and hIFNAR2c in a extended the binding data by transfecting wild-type and mutant hIF- murine background can mediate the antiviral response of human NAR2 cDNAs into murine L929 cells and have studied the effect of IFNs, but not an antiproliferative response (11). This suggests that several type I IFNs on mediating signal transduction. *Departments of Antibody Technology, Molecular Oncology, and Protein Engineer- Materials and Methods ing, Genentech Inc., South San Francisco, CA 94080; and †Department of Surgery, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121 Production of soluble hIFNAR1-IgG and various species of type Received for publication January 29, 1999. Accepted for publication May 4, 1999. 1 IFN The costs of publication of this article were defrayed in part by the payment of page hIFNAR2-IgG and various subspecies of hIFN-a were prepared as de- charges. This article must therefore be hereby marked advertisement in accordance scribed (14) with the following modification: A c-DNA encoding the hIF- with 18 U.S.C. Section 1734 solely to indicate this fact. NAR2-IgG molecules was constructed based on the ECD (residues 1–216) 1 Address correspondence and reprint requests to Dr. K. Jin Kim, Department of of hIFNAR2. hIFNAR2-IgG was expressed in 293 cells and the immuno- Antibody Technology, Genentech Inc., South San Francisco, CA 94080. E-mail ad- adhesin was purified using a protein A column. Human IFN-a2/a1 dress: [email protected] (IFN-a2 residues 1–62/a1 residues 64–166) (15, 16) were a gift from Dr. b 2 Abbreviations used in this paper: hIFN, human IFN; ECD, extracellular domain; M. J. Brunda (Hoffman-LaRoche, Nutley, NJ). hIFN- was obtained from hIFNAR, hIFN-a receptor; ISGF3, IFN-stimulated gene factor 3; RT, room Sigma (St. Louis, MO). The specific activities of the various type I IFNs temperature. are as follows: IFN-a2/a1(23 107 IU/mg), IFN-a1(33 107 IU/mg), Copyright © 1999 by The American Association of Immunologists 0022-1767/99/$02.00 The Journal of Immunology 767 Table I. General characteristics of mAbs to hIFNAR2 Affinityf a b c d e 21 mAb Isotype Cytometry Epitope Western Blot IP Kd (pM) 1D3 IgG2a 11 A 1 ND 242 1F3 IgG2a 11 B 215 3B2 IgG1 11 B 21ND 3B7 IgG2a 11 C 211 a The mAb isotype was determined using an isotype-specific goat anti-mouse Ig. b All mAbs were selected for positive staining of a 9D human B cell line. c mAbs were shown to recognize different epitopes by a competitive binding ELISA. d The immunoblot was performed using hIFNAR2-IgG reduced with DTT. e U266 cells were biotinylated using NHS-LC-biotin and lysed with 1% Nonidet P-40. Biotinylated hIFNAR2 was precipitated by mAbs bound to protein-G-4B Sepharose and separated on a 7.5% SDS-PAGE gel. Biotinylated hIFNAR2 transferred onto nitrocellulose paper was detected by HRP-strepavidin. f The affinity of mAbs were determined using the KinExA system. IFN-a2(23 107 IU/mg), IFN-a5(83 107 IU/mg), IFN-a8 (19 3 107 the unbound mAbs. The anti-IFNAR2 mAbs bound to beads were detected IU/mg), and IFN-b (1.5 3 105 IU/mg). by 1.5 ml of PE-labeled goat anti-mouse IgG. Unbound labeled material was removed by drawing 4.5 ml of 0.5 M NaCl through the bead pack over Downloaded from Generation of mAbs to hIFNAR2 a 3-min period. The equilibrium constant was calculated using the software provided by the manufacturer (Sapidyne). BALB/c mice were immunized with 2.5 mg of hIFNAR2-IgG into each hind footpad, and mAbs were generated as described (17). Three days after the final boost, popliteal lymph nodes were fused with myeloma cell line Electrophoretic mobility shift assay (EMSA) 3 P3 63Ag.U.1 (18). Culture supernatants were initially screened for their HeLa cells (5 3 105 cells) were incubated with each hIFN-a (25 ng/ml) in ability to bind to hIFNAR2-IgG, but not to CD4-IgG in a capture ELISA, 200 ml of DMEM for 30 min at 37°C.
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