7PDJ

R12E vFLIP mutant

Summary for 7PDJ

• Entry DOI: 10.2210/pdb7pdj/pdb
• Related: 3CL3 5LDE
• Descriptor: FLICE inhibitory protein (1 entity in total)
• Functional Keywords: kshv virus, tandem ded protein, nf-kappab activation, ikk kinase binding, ikkgamma, viral protein
• Biological source: Human herpesvirus 8 (HHV-8, Kaposi's sarcoma-associated herpesvirus)
• Total number of polymer chains: 6
• Total formula weight: 131264.20

Authors

Barrett, T.E. (deposition date: 2021-08-05, release date: 2022-05-11, Last modification date: 2024-02-07)

Primary citation

Bagneris, C.,Senthil Kumar, S.L.,Baratchian, M.,Britt, H.M.,Assafa, T.E.,Thalassinos, K.,Collins, M.K.,Barrett, T.E.
Mechanistic insights into the activation of the IKK kinase complex by the Kaposi's sarcoma herpes virus oncoprotein vFLIP.
J.Biol.Chem., 298:102012-102012, 2022

PubMed Abstract: Constitutive activation of the canonical NF-κB signaling pathway is a major factor in Kaposi's sarcoma-associated herpes virus pathogenesis where it is essential for the survival of primary effusion lymphoma. Central to this process is persistent upregulation of the inhibitor of κB kinase (IKK) complex by the virally encoded oncoprotein vFLIP. Although the physical interaction between vFLIP and the IKK kinase regulatory component essential for persistent activation, IKKγ, has been well characterized, it remains unclear how the kinase subunits are rendered active mechanistically. Using a combination of cell-based assays, biophysical techniques, and structural biology, we demonstrate here that vFLIP alone is sufficient to activate the IKK kinase complex. Furthermore, we identify weakly stabilized, high molecular weight vFLIP-IKKγ assemblies that are key to the activation process. Taken together, our results are the first to reveal that vFLIP-induced NF-κB activation pivots on the formation of structurally specific vFLIP-IKKγ multimers which have an important role in rendering the kinase subunits active through a process of autophosphorylation. This mechanism of NF-κB activation is in contrast to those utilized by endogenous cytokines and cellular FLIP homologues.

PubMed: 35525271
DOI: 10.1016/j.jbc.2022.102012

Experimental method

X-RAY DIFFRACTION (4.2 Å)