NMR Mapping of the IFNAR1-EC Binding Site on IFNalpha2 Reveals Allosteric Changes in the IFNAR2-EC Binding Site

Overview

Journal Biochemistry

Specialty Biochemistry

Date 2010 Jan 6

PMID 20047337

Citations 9

Authors

Sabine Ruth Akabayov

Zohar Biron

Peter Lamken

Jacob Piehler

Jacob Anglister

Affiliations

Soon will be listed here.

Abstract

All type I interferons (IFNs) bind to a common cell-surface receptor consisting of two subunits. IFNs initiate intracellular signal transduction cascades by simultaneous interaction with the extracellular domains of its receptor subunits, IFNAR1 and IFNAR2. In this study, we mapped the surface of IFNalpha2 interacting with the extracellular domain of IFNAR1 (IFNAR1-EC) by following changes in or the disappearance of the (1)H-(15)N TROSY-HSQC cross peaks of IFNalpha2 caused by the binding of the extracellular domain of IFNAR1 (IFNAR1-EC) to the binary complex of IFNalpha2 with IFNAR2-EC. The NMR study of the 89 kDa complex was conducted at pH 8 and 308 K using an 800 MHz spectrometer. IFNAR1 binding affected a total of 47 of 165 IFNalpha2 residues contained in two large patches on the face of the protein opposing the binding site for IFNAR2 and in a third patch located on the face containing the IFNAR2 binding site. The first two patches form the IFNAR1 binding site, and one of these matches the IFNAR1 binding site previously identified by site-directed mutagenesis. The third patch partially matches the IFNalpha2 binding site for IFNAR2-EC, indicating allosteric communication between the binding sites for the two receptor subunits.

Citing Articles

High efficacy of huCD20-targeted AcTaferon in humanized patient derived xenograft models of aggressive B cell lymphoma.

Daneels W, Van Parys A, Huyghe L, Rogge E, De Rouck S, Christiaen R Exp Hematol Oncol. 2024; 13(1):59.

PMID: 38831452 PMC: 11145843. DOI: 10.1186/s40164-024-00524-4.

Differential levels of IFNα subtypes in autoimmunity and viral infection.

Bondet V, Rodero M, Posseme C, Bost P, Decalf J, Haljasmagi L Cytokine. 2021; 144:155533.

PMID: 33941444 PMC: 7614897. DOI: 10.1016/j.cyto.2021.155533.

Site-selective protein conjugation at histidine.

Peciak K, Laurine E, Tommasi R, Choi J, Brocchini S Chem Sci. 2019; 10(2):427-439.

PMID: 30809337 PMC: 6354831. DOI: 10.1039/c8sc03355b.

The molecular basis for differential type I interferon signaling.

Schreiber G J Biol Chem. 2017; 292(18):7285-7294.

PMID: 28289098 PMC: 5418031. DOI: 10.1074/jbc.R116.774562.

Type-1 interferons contribute to oxygen glucose deprivation induced neuro-inflammation in BE(2)M17 human neuroblastoma cells.

Minter M, Zhang M, Ates R, Taylor J, Crack P J Neuroinflammation. 2014; 11:43.

PMID: 24602263 PMC: 3995960. DOI: 10.1186/1742-2094-11-43.

References

Roisman L, Piehler J, Trosset J, Scheraga H, Schreiber G . Structure of the interferon-receptor complex determined by distance constraints from double-mutant cycles and flexible docking. Proc Natl Acad Sci U S A. 2001; 98(23):13231-6. PMC: 60853. DOI: 10.1073/pnas.221290398. View

Goldman L, Cutrone E, Dang A, Hao X, Lim J, Langer J . Mapping human interferon-alpha (IFN-alpha 2) binding determinants of the type I interferon receptor subunit IFNAR-1 with human/bovine IFNAR-1 chimeras. Biochemistry. 1998; 37(37):13003-10. DOI: 10.1021/bi980073j. View

Hu R, Bekisz J, Schmeisser H, McPhie P, Zoon K . Human IFN-alpha protein engineering: the amino acid residues at positions 86 and 90 are important for antiproliferative activity. J Immunol. 2001; 167(3):1482-9. DOI: 10.4049/jimmunol.167.3.1482. View

Krause C, Pestka S . Evolution of the Class 2 cytokines and receptors, and discovery of new friends and relatives. Pharmacol Ther. 2005; 106(3):299-346. DOI: 10.1016/j.pharmthera.2004.12.002. View

Bernat B, Pal G, Sun M, Kossiakoff A . Determination of the energetics governing the regulatory step in growth hormone-induced receptor homodimerization. Proc Natl Acad Sci U S A. 2003; 100(3):952-7. PMC: 298707. DOI: 10.1073/pnas.0235023100. View

Ozbek S, Grotzinger J, Krebs B, Fischer M, Wollmer A, Jostock T . The membrane proximal cytokine receptor domain of the human interleukin-6 receptor is sufficient for ligand binding but not for gp130 association. J Biol Chem. 1998; 273(33):21374-9. DOI: 10.1074/jbc.273.33.21374. View

Klaus W, Gsell B, Labhardt A, Wipf B, Senn H . The three-dimensional high resolution structure of human interferon alpha-2a determined by heteronuclear NMR spectroscopy in solution. J Mol Biol. 1998; 274(4):661-75. DOI: 10.1006/jmbi.1997.1396. View

Karpusas M, Nolte M, Benton C, Meier W, Lipscomb W, Goelz S . The crystal structure of human interferon beta at 2.2-A resolution. Proc Natl Acad Sci U S A. 1997; 94(22):11813-8. PMC: 23607. DOI: 10.1073/pnas.94.22.11813. View

Gent J, van den Eijnden M, van Kerkhof P, Strous G . Dimerization and signal transduction of the growth hormone receptor. Mol Endocrinol. 2003; 17(5):967-75. DOI: 10.1210/me.2002-0261. View

10.

Chill J, Quadt S, Anglister J . NMR backbone dynamics of the human type I interferon binding subunit, a representative cytokine receptor. Biochemistry. 2004; 43(31):10127-37. DOI: 10.1021/bi049606g. View

11.

Cunningham B, Ultsch M, de Vos A, Mulkerrin M, Clauser K, Wells J . Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science. 1991; 254(5033):821-5. DOI: 10.1126/science.1948064. View

12.

Uze G, Schreiber G, Piehler J, Pellegrini S . The receptor of the type I interferon family. Curr Top Microbiol Immunol. 2007; 316:71-95. DOI: 10.1007/978-3-540-71329-6_5. View

13.

Pan M, Kalie E, Scaglione B, Raveche E, Schreiber G, Langer J . Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists. Biochemistry. 2008; 47(46):12018-27. DOI: 10.1021/bi801588g. View

14.

Kalie E, Jaitin D, Abramovich R, Schreiber G . An interferon alpha2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitumor activities. J Biol Chem. 2007; 282(15):11602-11. DOI: 10.1074/jbc.M610115200. View

15.

Piehler J, Roisman L, Schreiber G . New structural and functional aspects of the type I interferon-receptor interaction revealed by comprehensive mutational analysis of the binding interface. J Biol Chem. 2000; 275(51):40425-33. DOI: 10.1074/jbc.M006854200. View

16.

Lamken P, Gavutis M, Peters I, Van der Heyden J, Uze G, Piehler J . Functional cartography of the ectodomain of the type I interferon receptor subunit ifnar1. J Mol Biol. 2005; 350(3):476-88. DOI: 10.1016/j.jmb.2005.05.008. View

17.

LARKIN M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H . Clustal W and Clustal X version 2.0. Bioinformatics. 2007; 23(21):2947-8. DOI: 10.1093/bioinformatics/btm404. View

18.

Li Z, Strunk J, Lamken P, Piehler J, Walz T . The EM structure of a type I interferon-receptor complex reveals a novel mechanism for cytokine signaling. J Mol Biol. 2008; 377(3):715-24. PMC: 2577817. DOI: 10.1016/j.jmb.2007.12.005. View

19.

Senda T, Shimazu T, Matsuda S, Kawano G, Shimizu H, Nakamura K . Three-dimensional crystal structure of recombinant murine interferon-beta. EMBO J. 1992; 11(9):3193-201. PMC: 556852. DOI: 10.1002/j.1460-2075.1992.tb05396.x. View

20.

Johnson B, Blevins R . NMR View: A computer program for the visualization and analysis of NMR data. J Biomol NMR. 2012; 4(5):603-14. DOI: 10.1007/BF00404272. View