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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK
Virus-Cell Interactions I Abstract 23
INSIGHTS INTO KSHV ACTIVATION OF THE IKK SIGNALOSOME: CRYSTAL
STRUCTURE OF A VFLIP-IKKγ COMPLEX.
Claire Bagnéris, Alexander V Ageichik, Nora Cronin, Bonnie Wallace, Mary Collins, Chris
Boshoff, Gabriel Waksman and Tracey Barrett 1
1
Institute of Structural and Molecular Biology, School of Crystallography, Birkbeck
College, Malet Street, London WC1E 7HX, UK.
Abstract
During the latent phase of Kaposi Sarcoma Herpes virus (KSHV) infection, a limited
number of genes are expressed that are pivotal to viral propagation and survival.
Amongst them is ks-vFLIP whose over-expression has been directly linked to Kaposi
Sarcoma (KS) and other lymphoproliferative malignancies. ks-vFLIP shares considerable
homology with the human cellular FLIPs that have a key anti-apoptotic role, but by
contrast operates via a mechanism that involves subversion of the canonical NF-κB
transcriptional pathway (implicated in diverse cellular processes that include immune
activation and cellular growth). This is achieved through a direct interaction with IKKγ,
the regulatory component of the IKK complex or signalosome, and results in the normally
tightly regulated pathway being rendered constitutively active. As a consequence, the
expression of genes associated with anti-apoptosis, inflammation and oncogenesis are
aberrantly up-regulated. In order to establish the molecular basis underpinning ks-vFLIP
constitutive activation of the canonical NF-κB pathway, we have determined the crystal
structure of ks-vFLIP bound to an IKKγ fragment incorporating the ks-vFLIP recognition
motif. This first structure of a ks-vFLIP-IKKγ complex reveals an extensive ks-vFLIP-IKKγ
interface that has been probed using site directed mutagenesis to confirm the roles of
key amino acids in mediating the ks-vFLIP-IKKγ interaction. In addition, these have been
shown to be essential for ks-vFLIP induced activation of the canonical NF-κB pathway.
Our structure thus provides a framework for the design of novel therapeutics aimed at
the treatment of KS and related pathologies.
Presenting author Email: t.barrett@mail.cryst.bbk.ac.uk
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