Elucidation of the Basic Three-Dimensional Structure of Type I Interferons and Its Functional and Evolutionary Implications

Mitsui, Yukio; Senda, Toshiya

doi:10.1089/jir.1997.17.319

Cited by 17 publications

(10 citation statements)

References 37 publications

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“…Our limited studies in 2fTGH cells confirm this observation. We found that IFN-a2, IFN-a8, IFN-a288, and IFN-b showed substantial differences in the kinetics of gene induction when the IFN-inducible genes b-R1, [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27], and ISG 56K were studied. Further experiments examining more IFN-inducible genes will be required to determine if this phenomenon applies to all ISGs or just to a small subset.…”

Section: Discussionmentioning

confidence: 99%

“…The face consisting of the A and C helices interacts with IFNAR-1, whereas IFNAR-2 binds to the opposite side of the IFN molecule consisting of the A-B loop and the D helix. (16)(17)(18) Binding of IFN to its receptor leads to activation of the associated Janus kinases (Tyk2 and Jak1). Once activated (either by an allosteric change in the receptor or by receptor oligomerization), the kinases phosphorylate tyrosine motifs in the cytoplasmic domain of the receptor, leading to the recruitment and subsequent phosphorylation of the Stat proteins.…”

Section: Introductionmentioning

confidence: 99%

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Activity of Hybrid Type I Interferons in Cells Lacking Tyk2: A Common Region of IFN-α8 Induces a Response, but IFN-α2/8 Hybrids Can Behave Like IFN-β

Platis

Foster

2003

Journal of Interferon & Cytokine Research

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Type I interferons (IFNs) are a family of pleiotropic cytokines with antiviral, antiproliferative, and immunomodulatory properties. The type I IFN family consists of 12 IFN-alpha subtypes, IFN-beta, and IFN-omega. Cells lacking the receptor-associated protein kinase Tyk2 (U1A) are responsive only to IFN-beta and partially to IFN-alpha8. We constructed a series of IFN-alpha2/alpha8 hybrids and mutants and identified the region within IFN-alpha8 responsible for its activity in Tyk2-deficient cells. The same domain mediates the interactions between IFN and IFN-alpha receptor (IFNAR) in Tyk2-complemented and Tyk2-deficient cells (U1A). The presence or absence of Tyk2 altered the inhibitory effects of anti-IFNAR antibodies, suggesting that the IFN-alpha binding domain on IFNAR is altered by the presence of Tyk2. The activity of IFN-beta was not significantly affected by the deletion of Tyk2, and, surprisingly, one of our IFN-alpha2/alpha8 hybrids (IFN-alpha288) behaved like IFN-beta in a number of assays that distinguish IFN-alphas from IFN-beta. This suggests that this hybrid mimics the interactions of IFN-beta with the receptor and also suggests the existence of a distinct binding site(s) on IFNAR for IFN-beta and some hybrid IFN-alphas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activity of Hybrid Type I Interferons in Cells Lacking Tyk2: A Common Region of IFN-α8 Induces a Response, but IFN-α2/8 Hybrids Can Behave Like IFN-β

Platis

Foster

2003

Journal of Interferon & Cytokine Research

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“…There are a large number of reports on the structure-function relationship of these IFNs (7)(8)(9)(10)(11)(12)(13)(14). To elucidate the mechanism by which IFNs bind to and activate their receptor, detailed structureactivity studies are required.…”

Section: Nterferon (Ifn)-␣ Ifn-␤ and Ifn-(type 1 Ifn) Constitutementioning

confidence: 99%

Human IFN-α Protein Engineering: The Amino Acid Residues at Positions 86 and 90 Are Important for Antiproliferative Activity

Bekisz

Schmeisser

et al. 2001

The Journal of Immunology

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Human IFN-α is a family of structurally related proteins that exhibit a wide range of antiproliferative activities. To understand the structural basis for these different antiproliferative activities, eight recombinant human IFN-α hybrids (HY) of α21a/α2c (HY-4, HY-5) and mutants (site-directed mutagenesis (SDM)-1, 2 and cassette mutagenesis (CM)-1, 2, 3, and 4) have been expressed, purified, and characterized. The data showed that the amino acid region 81–95 is important for antiproliferative activity. Site-directed mutagenesis and cassette mutagenesis studies showed that if serine (S) 86 and asparagine (N) 90 were replaced by tyrosine (Y), the antiproliferative activity was increased. We have also observed that if Y86 was replaced by isoleucine (I), the antiproliferative activity was comparable. However, if Y86 was replaced by aspartic acid (D), lysine (K), or alanine (A), the antiproliferative activity was substantially decreased. Our results indicate that Y and/or I at position 86 and Y at position 90 are very important in antiproliferative activity of human IFN-α. Circular dichroism spectra showed that the amino acid replacements at position 86 did not change the secondary structure. Thus the biological activity changes among those mutants do not appear to be due to conformational changes. The results also suggest that hydrophobic residue(s) at position 86 may be important for the interaction of the molecule with its receptor. The competitive binding data correlated with the antiproliferative activity. The N-terminal region of the molecule and the hydrophobic residues (including Y and I) on the C-helix region at positions 86 and/or 90 are important for binding and antiproliferative activities of human IFN-αs.

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“…2 In spite of the high homology of the different sub-types, their biological activities, among them anti-proliferative, antiviral, and immunomodulation, differ notably. 5,6 The structures of several type I interferons have been solved including murine IFNb (1IFA, 1RMI), 7 human IFNb (1AU1), 8 human IFNa2 (1RH2, 1ITF), 9,10 and ovine IFNt (1B5L). 11 Structurally, interferons are members of the a-helical cytokine family.…”

Section: Introductionmentioning

confidence: 99%

Mutational Analysis of the IFNAR1 Binding Site on IFNα2 Reveals the Architecture of a Weak Ligand–Receptor Binding-site

Roisman

Jaitin

Baker

et al. 2005

Journal of Molecular Biology

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Elucidation of the Basic Three-Dimensional Structure of Type I Interferons and Its Functional and Evolutionary Implications

Cited by 17 publications

References 37 publications

Activity of Hybrid Type I Interferons in Cells Lacking Tyk2: A Common Region of IFN-α8 Induces a Response, but IFN-α2/8 Hybrids Can Behave Like IFN-β

Activity of Hybrid Type I Interferons in Cells Lacking Tyk2: A Common Region of IFN-α8 Induces a Response, but IFN-α2/8 Hybrids Can Behave Like IFN-β

Human IFN-α Protein Engineering: The Amino Acid Residues at Positions 86 and 90 Are Important for Antiproliferative Activity

Mutational Analysis of the IFNAR1 Binding Site on IFNα2 Reveals the Architecture of a Weak Ligand–Receptor Binding-site

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