Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Frontiers Media SA full text link Frontiers Media SA Free PMC article
Full text links

Actions

Review
.2020 Nov 12:11:606489.
doi: 10.3389/fimmu.2020.606489. eCollection 2020.

The Role of Structure in the Biology of Interferon Signaling

Affiliations
Review

The Role of Structure in the Biology of Interferon Signaling

Mark R Walter. Front Immunol..

Abstract

Interferons (IFNs) are a family of cytokines with the unique ability to induce cell intrinsic programs that enhance resistance to viral infection. Induction of an antiviral state at the cell, tissue, organ, and organismal level is performed by three distinct IFN families, designated as Type-I, Type-II, and Type-III IFNs. Overall, there are 21 human IFNs, (16 type-I, 12 IFNαs, IFNβ, IFNϵ, IFNκ, and IFNω; 1 type-II, IFNγ; and 4 type-III, IFNλ1, IFNλ2, IFNλ3, and IFNλ4), that induce pleotropic cellular activities essential for innate and adaptive immune responses against virus and other pathogens. IFN signaling is initiated by binding to distinct heterodimeric receptor complexes. The three-dimensional structures of the type-I (IFNα/IFNAR1/IFNAR2), type-II (IFNγ/IFNGR1/IFNGR2), and type-III (IFNλ3/IFNλR1/IL10R2) signaling complexes have been determined. Here, we highlight similar and unique features of the IFNs, their cell surface complexes and discuss their role in inducing downstream IFN signaling responses.

Keywords: IFN; IFN signaling; interferon; receptor complex; structure; type-I; type-II; type-III.

Copyright © 2020 Walter.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structures of IFN family members. Schematic, and ribbon diagrams, show the six secondary structural elements of the type-I(A), pdbid = 1AU, type-III(B), pdbid = 3HHC, and type-II(C), pdbid = 6E3K IFNs. IFN structures are rainbow colored from the N-terminus helix A (blue) to the C-terminal helix F (red).
Figure 2
Figure 2
Structures of the IFN Receptor Complexes. Ribbon diagrams of the type-III(A), pdbid = 5T5W, type-II(B), pdbid = 6E3K, and type-I(C), pdbid = 3SE4, receptor complexes. IFNs are rainbow colored as described in Figure 1. The β-strands of the high affinity receptor chains are colored green and low affinity chains are colored magenta. For the type-II IFNγ receptor complex, only one IFNγ subunit is shown to emphasize the similarity of “half” of the complex with the type-III IFN receptor complex. The separation of the C-termini of the type-III IFNλR1/IL-10R2 and type-II IFNGR1/IFNGR2 receptor chains, where they enter the membrane are 30Å and 22Å, respectively. A D2-D4 interaction was not observed in structures of the IFN/IFNAR1/IFNAR2 complex.
Figure 3
Figure 3
Subtle structural changes between IFNλ1/IFNλ3 alter IFNλR1 Contacts.(A) Alpha carbon diagram of the superposition of IFNλ1 and IFNλ3. The location of structural differences in the B loop regions of IFNλ1 and IFNλ3, as discussed in the text, are circled.(B) Enlargement of the B loop “proline flip” observed in IFNλ1 and IFNλ3 structures and its influence on the conformation of Arg-180IFNλ3 (green), where it makes a salt bridge with IFNλR1 Asp-91. In contrast, IFNλ1 Arg-175 (magenta) extends away from IFNλR1 Asp-91 towards the B loop.
Figure 4
Figure 4
Dimeric IFNγ/IFNGR1/IFNGR2 Complex. Ribbon diagram of the 1:2:2 IFNγ dimer/IFNGR1/IFNGR2 complex (pdbid = 6E3K). Two views of the complex are shown. The first is approximately perpendicular to the IFNγ twofold axis(A) and the second is parallel to the twofold axis(B).
Figure 5
Figure 5
Structural Models of the IFNAR1 D4 Domain.(A) Ribbon diagram of the type-I IFN (IFNω, blue)/IFNAR1 (orange)/IFNAR2 (yellow) complex structure (pdbid = 3SE4), which lacks the IFNAR1 D4 domain.(B) Superposition of the IFNλ3 (rainbow)/IFNλR1 (green)/IL10R2 (magenta) ternary complex on the IFN/IFNAR1/IFNAR2 structure positions the IL10R2 D2 domain (magenta), such that it could represent the transient location of the IFNAR1 D4 domain forming an IFNAR2 D2-IFNAR1 D4 stem interaction.(C) A second possible location of the human IFNAR1 D4 domain is shown by superimposing the murine IFNβ/IFNAR1 complex (pdbid = 3WCY) on the IFN/IFNAR1/IFNAR2 complex. The position of the modeled D4 domain (green), derived from the murine IFNβ/IFNAR1 structure is shown in green, and the location of the IFNAR1 D4 domain obtained from superimposing the IFNλ receptor complex is shown in magenta. Since the human IFNAR1 D4 domain does not form a stable D2-D4 interaction with IFNAR2, D4 may transition between green and magenta conformations to induce biological activity. The exact role of the D4 domain in IFN signal transduction remains unknown.
Figure 6
Figure 6
Structural Comparison of human and murine IFNβ.(A) Structural superposition of human IFNβ (colored as inFigure 1, pdbid = 1AU1) and murine IFNβ (wheat, pdbid = 1WU3), highlighting their distinct AB loop structures.(B) Structural superposition of murine and human IFNβ onto IFNα2 from the human IFNα2/IFNAR2 crystal structure. The resulting structural model results in steric clashes between the murine IFNβ AB loop and IFNAR2 binding loops, but not for the human IFNβ/IFNAR2 model. This structural analysis provides an explanation for the low affinity of the murine IFNβ/IFNAR2 interaction, compared to the high affinity human IFNβ/IFNAR2 interaction.
See this image and copyright information in PMC

References

    1. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci (1957) 147(927):258–67. 10.1098/rspb.1957.0048 - DOI - PubMed
    1. Wheelock EF. Interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin. Science (New York NY) (1965) 149(3681):310–1. 10.1126/science.149.3681.310 - DOI - PubMed
    1. Stewart WE. 2nd. Interferon nomenclature recommendations. J Infect Dis (1980) 142(4):643. 10.1093/infdis/142.4.643 - DOI - PubMed
    1. Radhakrishnan R, Walter LJ, Hruza A, Reichert P, Trotta PP, Nagabhushan TL, et al. Zinc mediated dimer of human interferon-alpha 2b revealed by X-ray crystallography. Structure (1996) 4(12):1453–63. 10.1016/S0969-2126(96)00152-9 - DOI - PubMed
    1. Karpusas M, Nolte M, Benton CB, Meier W, Lipscomb WN, 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. 10.1073/pnas.94.22.11813 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full text links
Frontiers Media SA full text link Frontiers Media SA Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp