Interaction of truncated human interferon <i>γ</i> variants with the interferon <i>γ</i> receptor: crucial importance of Arg-129

Haelewyn, Joost; Michiels, Lieve; Verhaert, Peter; Hoylaerts, Marc; Witters, Raphaël; Ley, Marc De

doi:10.1042/bj3240591

Cited by 16 publications

(15 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the C-terminal tail of IFN-␥ is not observed in three different IFN-␥R1/IFN-␥ crystal structures (14,16,17), suggesting that it forms transient interactions with IFN-␥R1 and is disordered in the time-averaged structures. Surface plasmon resonance (SPR) studies on murine IFN-␥ /IFN-␥BP ECTV and human IFN-␥/sIFN-␥R1 interactions are consistent with these structural observations (SI Table 3) (9,22,23). Specifically, removing the Lys128Arg129Lys130Arg131 sequence (KRKR region; Figs.…”

Section: Discussionsupporting

confidence: 61%

Structure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ-binding protein

Nuara

Walter²,

Logsdon³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Ectromelia virus (ECTV) encodes an IFN-␥-binding protein (IFN-␥BPectromelia virus ͉ immunomodulator ͉ interferon ͉ cytokine ͉ complex E ctromelia virus (ECTV) is an orthopoxvirus that causes mousepox, which closely resembles the genetic and disease characteristics of the human pathogen variola virus (VARV), the causative agent of smallpox (1). The genomes of all orthopoxviruses, including ECTV and VARV, encode proteins required for viral replication, as well as soluble cytokine-and chemokine-binding proteins, which disrupt the activation and recruitment of immune cells responsible for host antiviral responses (2, 3). The severity of smallpox and mousepox has been attributed to the effectiveness of these immunomodulatory proteins, which in many instances, exhibit significant homology to cellular receptors, suggesting they were captured and adapted to subvert host immune responses during poxvirus evolution.All orthopoxviruses express IFN-␥-binding proteins (IFN␥BPs) that efficiently block IFN-␥-mediated signaling cascades responsible for activating potent antiviral defense mechanisms. The importance of IFN-␥ in viral pathogenesis is demonstrated by studies in C57BL/6 mice, in which depletion of IFN-␥ by monoclonal antibody treatment, or disruption of the signaling pathway through genetic means, transforms benign ECTV infection into a lethal one (4, 5). In addition, the ectromelia virus IFN-␥BP (IFN-␥BP ECTV ) has been shown to be a critical virulence factor in BALB/c mice, in which ECTV infections are lethal but infections with an ECTV mutant lacking a functional IFN-␥BP ECTV are not (6).Orthopoxvirus IFN-␥BPs are Ϸ270-aa proteins that share Ͼ90% sequence identity with one another and Ϸ20% sequence identity with the extracellular region of the cellular IFN-␥R1 chains, often called the cytokine receptor homology region (CRHR). In contrast to cellular IFN-␥R1s, which exhibit species-specific binding to their cognate ligand, IFN-␥BPs exhibit relaxed IFN-␥-binding specificity (7, 8) (e.g., IFN-␥BP ECTV binds human, murine, rabbit, and bovine IFN-␥). This functional difference may have facilitated opportunistic viral infections in multiple hosts during the evolution of the virus.In contrast to the CRHR, the C-terminal Ϸ60 aa of the IFN-␥BPs share no identifiable sequence similarity with cellular proteins. Recent studies suggest that the C terminus mediates oligomerization of the IFN-␥-binding domains (9). However, there are conflicting reports about the quaternary structure of the molecules. For example, IFN-␥BPs encoded by VACV-WR (Western Reserve) and myxoma virus (M-T7) have been reported to form dimers and trimers, respectively (10, 11). In contrast to these reports, we have demonstrated recently that IFN-␥BPs from ECTV and VACV-B8R (Copenhagen strain) adopt larger oligomers in solution, likely tetramers, which are critical for antagonizing IFN-␥ activity (9).To address the basic mechanisms of IFN-␥ antagonism by orthopoxvirus IFN-␥BPs, we determined the crystal structure of IFN-␥BP ECTV bound to human IFN-␥. IFN-␥...

show abstract

Section: Discussionsupporting

confidence: 61%

Structure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ-binding protein

Nuara

Walter²,

Logsdon³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Thus it was teins III and V or on the ptrp2IFN DNA template for demonstrated that Arg129 was a functionally im-the gene encoding truncated protein IV. The amplificaportant amino acid residue for IFN-␥ interaction with tion was carried out in this case in the presence of its receptor (19). In addition, it was shown that a vari-anchor primer 7 and mutagenizing primers 5 (for variant of IFN-␥ with a deletion of 9 or 10 C-terminal amino ants IV and V) and 6 (variant III).…”

mentioning

confidence: 99%

“…On the confirmed by the nucleotide sequence between the other hand, removal of 11-16 C-terminal amino acid EcoRI and the PstI sites. To obtain the truncated genes, residues or mutations in the cluster Lys 128 -Arg-Lys-Arg amplification was similarly performed on the template entails a significant decrease or even a complete loss of plasmid ptrp2IFNmut for the genes encoding proof the IFN-␥ biological activity (7,(12)(13)(14)(15)(16)(17)(18)(19). Thus it was teins III and V or on the ptrp2IFN DNA template for demonstrated that Arg129 was a functionally im-the gene encoding truncated protein IV.…”

mentioning

confidence: 99%

Methods for Preparation of Recombinant Cytokine Proteins V. Mutant Analogues of Human Interferon-γ with Higher Stability and Activity

Pechenov

Tikhonov

Shingarova

et al. 2002

Protein Expression and Purification

View full text Add to dashboard Cite

“…The vIFNγbp made extensive contacts using six different receptor loops that bound to IFNγ on the A, B, and F helices as well as on the AB loop. However, in contrast to data that indicate that the host receptors do not make significant and high affinity contacts with the unstructured C‐terminal tail of IFNγ, the vIFNγbp made extensive contacts with this region . The decoy receptor engagement of the IFNγ C‐terminal region accounts for almost half of the buried surface area in the complex.…”

Section: Interference Of Interferonsmentioning

confidence: 63%

Subversion of cytokine networks by virally encoded decoy receptors

Epperson

Lee

Fremont

2012

Immunological Reviews

View full text Add to dashboard Cite

Summary During the course of evolution, viruses have captured or created a diverse array of open reading frames that encode for proteins that serve to evade and sabotage the host innate and adaptive immune responses, which would otherwise lead to their elimination. These viral genomes are some of the best textbooks of immunology ever written. The established arsenal of immunomodulatory proteins encoded by viruses is large and growing and includes specificities for virtually all known inflammatory pathways and targets. The focus of this review is on herpes and poxvirus-encoded cytokine and chemokine binding proteins that serve to undermine the coordination of host immune surveillance. Structural and mechanistic studies of these decoy receptors have provided a wealth of information, not only about viral pathogenesis but also about the inner workings of cytokine signaling networks.

show abstract

Interaction of truncated human interferon γ variants with the interferon γ receptor: crucial importance of Arg-129

Cited by 16 publications

References 20 publications

Structure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ-binding protein

Structure and mechanism of IFN-γ antagonism by an orthopoxvirus IFN-γ-binding protein

Methods for Preparation of Recombinant Cytokine Proteins V. Mutant Analogues of Human Interferon-γ with Higher Stability and Activity

Subversion of cytokine networks by virally encoded decoy receptors

Contact Info

Product

Resources

About