Crystal structure of a vFlip-IKKγ complex:: Insights into viral activation of the IKK signalosome

Key to the pathogenicity of several viruses is activation of the canonical nuclear factor-kappa B (NF-kappa B) 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 IKK gamma, an essential component of the IKK complex or signalosome. This interaction renders the canonical NF-kappa B 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 IKK gamma bound to ks-vFLIP at 3.2 angstrom. In addition to identifying and subsequently probing the ks-vFLIP-IKK gamma interface, we have also investigated the effects of a mutation implicated in the genetic disorder anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID).