Structural modeling of the N-terminal signal-receiving domain of I?B?.

ABSTRACT: The transcription factor nuclear factor-?B (NF-?B) exerts essential roles in many biological processes including cell growth, apoptosis and innate and adaptive immunity. The NF-?B inhibitor (I?B?) retains NF-?B in the cytoplasm and thus inhibits nuclear localization of NF-?B and its association with DNA. Recent protein crystal structures of the C-terminal part of I?B? in complex with NF-?B provided insights into the protein-protein interactions but could not reveal structural details about the N-terminal signal receiving domain (SRD). The SRD of I?B? contains a degron, formed following phosphorylation by I?B kinases (IKK). In current protein X-ray structures, however, the SRD is not resolved and assumed to be disordered. Here, we combined secondary structure annotation and domain threading followed by long molecular dynamics (MD) simulations and showed that the SRD possesses well-defined secondary structure elements. We show that the SRD contains 3 additional stable ?-helices supplementing the six ARDs present in crystallized I?B?. The I?B?/NF-?B protein-protein complex remained intact and stable during the entire simulations. Also in solution, free I?B? retains its structural integrity. Differences in structural topology and dynamics were observed by comparing the structures of NF-?B free and NF-?B bound I?B?-complex. This study paves the way for investigating the signaling properties of the SRD in the I?B? degron. A detailed atomic scale understanding of molecular mechanism of NF-?B activation, regulation and the protein-protein interactions may assist to design and develop novel chronic inflammation modulators.

SUBMITTER: Yazdi S 

PROVIDER: S-EPMC4477481 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature