Control protein switch found
Research from Dundee has revealed how a complex protein pivotal in the development of cancer, autoimmune disease and viral infection is activated. The study answers a key question about how NF-KB – nuclear factor kappa-light-chain-enhancer of activated B cells – is activated. The protein complex controls the transcription of DNA and plays a key role in regulating the immune response to infection. It is found in almost all animal cells, and its incorrect regulation is linked to cancer, inflammatory and autoimmune disease. “NF-KB has been the subject of a vast amount of research for many years as it plays a critical role in inflammatory disease and cancer,” said Sir Philip Cohen from the University of Dundee. “It has been known for some time that the protein is activated by a kinase called IKK_ but there has been split opinion with regards to how the kinase itself it switched on.” The research, published in Biochemical Journal, confirmed that another kinase TAK1 is required to prime IKK_ for activation by autophosphorylation, but that alone is not enough to switch on IKK_. “Two other events need to happen in addition, namely the formation of an unusual type of ubiquitin chain and its attachment to IKK_ and then the addition of a second phosphate group on to IKK_ which is remarkably carried out by IKK_ itself,” said Cohen. “It is only then that IKK_ becomes competent to switch on NF-KB.” “This is complex biochemistry, but working out the details of how proteins are switched on and off is how new ways to develop improved drugs to treat disease are identified,” added Cohen. “For example, the enzyme that makes the ubiquitin chains needed to activate IKK_ could now be targeted to develop a drug to treat inflammatory disease. The research was conducted at the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU) at Dundee. An unexpected twist to the activation of IKK_: TAK1 primes IKK_ for activation by autophosphorylation
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