Myxoma virus T2 protein, a tumor necrosis factor (TNF) receptor homolog, is secreted as a monomer and dimer that each bind rabbit TNFα, but the dimer is a more potent TNF inhibitor

Martha Schreiber, Krishna Rajarathnam, Grant McFadden

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Abstract

The myxoma virus T2 (M-T2) gene expresses a secreted protein that contains significant sequence similarity to the ligand binding domains of the cellular tumor necrosis factor (TNF) receptors, specifically inhibits the cytolytic activity of rabbit TNFα and is an important virulence factor for myxoma virus infection in rabbits. M-T2 protein was overexpressed from vaccinia virus vectors, purified to apparent homogeneity, and found to specifically protect mouse and rabbit cells from lysis by rabbit TNFα at molar ratios comparable with the soluble versions of the host tumor necrosis factor receptors. M-T2 secreted from virus-infected cells is detected as both a monomer and a disulfide-linked dimer, both of which were shown by Scatchard analysis to bind rabbit TNFα (K(d) values of 170 pM and 195 pM, respectively), values that are comparable with the affinities of mammalian TNFs with their receptors. In contrast to the rabbit ligand, M-T2 interacts with mouse TNFα with a much lower affinity, K(d) of 1.7 nM, and was unable to inhibit the cytolytic activity of this ligand on mouse cells. Although both monomeric and dimeric forms bound rabbit TNFα with comparable affinity, the dimeric M-T2 protein was a far more potent inhibitor of rabbit TNFα, presumably because it can more effectively prevent dimerization of TNF receptors than can the M-T2 monomer.

Original languageEnglish (US)
Pages (from-to)13333-13341
Number of pages9
JournalJournal of Biological Chemistry
Volume271
Issue number23
DOIs
StatePublished - 1996
Externally publishedYes

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Myxoma virus
Tumor Necrosis Factor Receptors
Viruses
Dimers
Tumor Necrosis Factor-alpha
Monomers
Rabbits
Proteins
Ligands
Vaccinia virus
Dimerization
Virulence Factors
Virus Diseases
Disulfides
Genes

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "Myxoma virus T2 protein, a tumor necrosis factor (TNF) receptor homolog, is secreted as a monomer and dimer that each bind rabbit TNFα, but the dimer is a more potent TNF inhibitor",
abstract = "The myxoma virus T2 (M-T2) gene expresses a secreted protein that contains significant sequence similarity to the ligand binding domains of the cellular tumor necrosis factor (TNF) receptors, specifically inhibits the cytolytic activity of rabbit TNFα and is an important virulence factor for myxoma virus infection in rabbits. M-T2 protein was overexpressed from vaccinia virus vectors, purified to apparent homogeneity, and found to specifically protect mouse and rabbit cells from lysis by rabbit TNFα at molar ratios comparable with the soluble versions of the host tumor necrosis factor receptors. M-T2 secreted from virus-infected cells is detected as both a monomer and a disulfide-linked dimer, both of which were shown by Scatchard analysis to bind rabbit TNFα (K(d) values of 170 pM and 195 pM, respectively), values that are comparable with the affinities of mammalian TNFs with their receptors. In contrast to the rabbit ligand, M-T2 interacts with mouse TNFα with a much lower affinity, K(d) of 1.7 nM, and was unable to inhibit the cytolytic activity of this ligand on mouse cells. Although both monomeric and dimeric forms bound rabbit TNFα with comparable affinity, the dimeric M-T2 protein was a far more potent inhibitor of rabbit TNFα, presumably because it can more effectively prevent dimerization of TNF receptors than can the M-T2 monomer.",
author = "Martha Schreiber and Krishna Rajarathnam and Grant McFadden",
year = "1996",
doi = "10.1074/jbc.271.23.13333",
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T1 - Myxoma virus T2 protein, a tumor necrosis factor (TNF) receptor homolog, is secreted as a monomer and dimer that each bind rabbit TNFα, but the dimer is a more potent TNF inhibitor

AU - Schreiber, Martha

AU - Rajarathnam, Krishna

AU - McFadden, Grant

PY - 1996

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AB - The myxoma virus T2 (M-T2) gene expresses a secreted protein that contains significant sequence similarity to the ligand binding domains of the cellular tumor necrosis factor (TNF) receptors, specifically inhibits the cytolytic activity of rabbit TNFα and is an important virulence factor for myxoma virus infection in rabbits. M-T2 protein was overexpressed from vaccinia virus vectors, purified to apparent homogeneity, and found to specifically protect mouse and rabbit cells from lysis by rabbit TNFα at molar ratios comparable with the soluble versions of the host tumor necrosis factor receptors. M-T2 secreted from virus-infected cells is detected as both a monomer and a disulfide-linked dimer, both of which were shown by Scatchard analysis to bind rabbit TNFα (K(d) values of 170 pM and 195 pM, respectively), values that are comparable with the affinities of mammalian TNFs with their receptors. In contrast to the rabbit ligand, M-T2 interacts with mouse TNFα with a much lower affinity, K(d) of 1.7 nM, and was unable to inhibit the cytolytic activity of this ligand on mouse cells. Although both monomeric and dimeric forms bound rabbit TNFα with comparable affinity, the dimeric M-T2 protein was a far more potent inhibitor of rabbit TNFα, presumably because it can more effectively prevent dimerization of TNF receptors than can the M-T2 monomer.

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