Structure of M11L: A myxoma virus structural homolog of the apoptosis inhibitor, Bcl-2.
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.
Douglas
Andrew E
AE
Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720, USA.
Corbett
Kevin D
KD
Berger
James M
JM
McFadden
Grant
G
Handel
Tracy M
TM
D000595:Amino Acid Sequence; D017209:Apoptosis; D018360:Crystallography, X-Ray; D005454:Fluorescence Polarization; D008969:Molecular Sequence Data; D009233:Myxoma virus / Q000737:chemistry*; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000737:chemistry*
D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins