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Structure of M11L: A myxoma virus structural homolog of the apoptosis inhibitor, Bcl-2.

ABSTRACT: Apoptosis of virally infected cells is an innate host mechanism used to prevent viral spread. However, viruses have evolved a number of proteins that function to modulate the apoptotic cascades and thereby favor productive viral replication. One such antiapoptotic protein, myxoma virus M11L, has been shown to inhibit mitochondrial-dependent apoptosis by binding to and blocking the two executioner proteins Bak and Bax. Since M11L has no obvious sequence homology with Bcl-2 or Bcl-x(L), the normal cellular inhibitors for Bak and Bax, and the structure of M11L has not been solved, the mode of binding to Bak and Bax is not known. In order to understand how M11L functions, the crystal structure of M11L was solved to 2.91 A. Despite the lack of sequence similarity, M11L is a structural homolog of Bcl-2. Studies using a peptide derived from Bak indicate that M11L binds to Bak with a similar affinity (4.9 +/- 0.3 microM) to the published binding affinities of Bcl-2 and Bcl-x(L) to the same peptide (12.7 microM and 0.5 microM, respectively), indicating that M11L inhibits apoptosis by mimicking and competing with host proteins for the binding of Bak and Bax. The structure provides important insight into how myxoma virus and other poxviruses facilitate viral dissemination by inhibiting mitochondrial dependent apoptosis.

SUBMITTER: Douglas AE

PROVIDER: S-EPMC2203349 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Structure of M11L: A myxoma virus structural homolog of the apoptosis inhibitor, Bcl-2.

Douglas Andrew E AE Corbett Kevin D KD Berger James M JM McFadden Grant G Handel Tracy M TM

Protein science : a publication of the Protein Society 20070401 4

Apoptosis of virally infected cells is an innate host mechanism used to prevent viral spread. However, viruses have evolved a number of proteins that function to modulate the apoptotic cascades and thereby favor productive viral replication. One such antiapoptotic protein, myxoma virus M11L, has been shown to inhibit mitochondrial-dependent apoptosis by binding to and blocking the two executioner proteins Bak and Bax. Since M11L has no obvious sequence homology with Bcl-2 or Bcl-x(L), the normal ...[more]

PMID: 17384234

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Project description:Myxomatosis is a recurrent problem on rabbit farms throughout Europe despite the success of vaccines. To identify gene variations of field and vaccine strains that may be responsible for changes in virulence, immunomodulation, and immunoprotection, the genomes of 6 myxoma virus (MYXV) strains were sequenced: German field isolates Munich-1, FLI-H, 2604, and 3207; vaccine strain MAV; and challenge strain ZA. The analyzed genomes ranged from 147.6 kb (strain MAV) to 161.8 kb (strain 3207). All sequences were affected by several mutations, covering 24 to 93 open reading frames (ORFs) and resulted in amino acid substitutions, insertions, or deletions. Only strains Munich-1 and MAV revealed the deletion of 10 ORFs (M007L to M015L) and 11 ORFs (M007L to M008.1L and M149R to M008.1R), respectively. Major differences were observed in the 27 immunomodulatory proteins encoded by MYXV. Compared to the reference strain Lausanne, strains FLI-H, 2604, 3207, and ZA showed the highest amino acid identity (>98.4%). In strains Munich-1 and MAV, deletion of 5 and 10 ORFs, respectively, was observed, encoding immunomodulatory proteins with ankyrin repeats or members of the family of serine protease inhibitors. Furthermore, putative immunodominant surface proteins with homology to vaccinia virus (VACV) were investigated in the sequenced strains. Only strain MAV revealed above-average frequencies of amino acid substitutions and frameshift mutations. Finally, we performed recombination analysis and found signs of recombination in vaccine strain MAV. Phylogenetic analysis showed a close relationship of strain MAV and the MSW strain of Californian MYXV. However, in a challenge model, strain MAV provided full protection against lethal challenges with strain ZA. Myxoma virus (MYXV) is pathogenic for European rabbits and two North American species. Due to sophisticated strategies in immune evasion and oncolysis, MYXV is an important model virus for immunological and pathological research. In its natural hosts, MYXV causes a benign infection, whereas in European rabbits, it causes the lethal disease myxomatosis. Since the introduction of MYXV into Australia and Europe for the biological control of European rabbits in the 1950s, a coevolution of host and pathogen has started, selecting for attenuated virus strains and increased resistance in rabbits. Evolution of viruses is a continuous process and influences the protective potential of vaccines. In our analyses, we sequenced 6 MYXV field, challenge, and vaccine strains. We focused on genes encoding proteins involved in virulence, host range, immunomodulation, and envelope composition. Genes affected most by mutations play a role in immunomodulation. However, attenuation cannot be linked to individual mutations or gene disruptions.

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Structure of M11L: A myxoma virus structural homolog of the apoptosis inhibitor, Bcl-2.

Publications

Structure of M11L: A myxoma virus structural homolog of the apoptosis inhibitor, Bcl-2.

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