4dn5

Publication Abstract from PubMed

NF-kappaB-inducing kinase (NIK) is a central component in the non-canonical NF-kappaB signaling pathway. Excessive NIK activity is implicated in various disorders, such as autoimmune conditions and cancers. Here, we report the first crystal structure of truncated human NIK in complex with adenosine 5'-O-(thiotriphosphate) at a resolution of 2.5 A. This truncated protein is a catalytically active construct, including an N-terminal extension of 60 residues prior to the kinase domain, the kinase domain, and 20 residues afterward. The structure reveals that the NIK kinase domain assumes an active conformation in the absence of any phosphorylation. Analysis of the structure uncovers a unique role for the N-terminal extension sequence, which stabilizes helix alphaC in the active orientation and keeps the kinase domain in the catalytically competent conformation. Our findings shed light on the long-standing debate over whether NIK is a constitutively active kinase. They also provide a molecular basis for the recent observation of gain-of-function activity for an N-terminal deletion mutant (DeltaN324) of NIK, leading to constitutive non-canonical NF-kappaB signaling with enhanced B-cell adhesion and apoptosis resistance.

Structure of the nuclear factor kappaB-inducing kinase (NIK) kinase domain reveals a constitutively active conformation.,Liu J, Sudom A, Min X, Cao Z, Gao X, Ayres M, Lee F, Cao P, Johnstone S, Plotnikova O, Walker N, Chen G, Wang Z J Biol Chem. 2012 Aug 10;287(33):27326-34. Epub 2012 Jun 20. PMID:22718757^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.