Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome.
Key to the pathogenicity of several viruses is activation of the canonical nuclear factor-kappaB (NF-kappaB) transcriptional pathway. Subversion of this tightly regulated mechanism is achieved through the production of host mimetic viral proteins that deregulate the transcription process. One such protein is ks-vFLIP (produced by the Kaposi's sarcoma herpes virus [KSHV]), which associates with IKKgamma, an essential component of the IKK complex or signalosome. This interaction renders the canonical NF-kappaB pathway constitutively active and has been linked to Kaposi's sarcoma and other malignancies. In order to elucidate the molecular basis underpinning ks-vFLIP-induced activation of the IKK signalosome, we have determined the crystal structure of a complex involving a fragment of IKKgamma bound to ks-vFLIP at 3.2 A. In addition to identifying and subsequently probing the ks-vFLIP-IKKgamma interface, we have also investigated the effects of a mutation implicated in the genetic disorder anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID).
Institute of Structural and Molecular Biology, School of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK.
Claire
C
Bagnéris
Alexander V
AV
Ageichik
Nora
N
Cronin
Bonnie
B
Wallace
Mary
M
Collins
Chris
C
Boshoff
Gabriel
G
Waksman
Tracey
T
Barrett
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D015398:Signal Transduction; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8; D051550:I-kappa B Kinase