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Research Themes Cancer

Cancer Networks: IFI16-mediated p53 Activation

SBKB [doi:10.1038/sbkb.2012.169]
Featured Article - November 2013
Short description: Structural and functional analyses of the p53-binding HIN domains of IFI16 reveal their mechanism of action.

Structure of the p53-binding HIN-A domain of IFI16 comprising two OB-fold subdomains that act as a single unit. Figure courtesy of Cheryl Arrowsmith.

Interferon-inducible protein 16 (IFI16) is one of four members of the HIN-200 family, which is characterized by the presence of a 200-amino acid signature motif called the HIN domain. HIN domains have been implicated in DNA binding as well as protein-protein interactions with numerous transcription factors, including tumor suppressor p53. IFI16 is widely expressed and has been reported to regulate p53-mediated transcriptional activation; reduced IFI16 expression has been observed in several human cancers. The overexpression of IFI16 could induce apoptosis in human bladder carcinoma cells in a p53-dependent manner.

To gain further insight into the molecular mechanism of p53 regulation by the HIN-200 protein family, Arrowsmith and colleagues (PSI NESG) determined the crystal structures of the individual HIN-A (PDB 2OQ0) and HIN-B (PDB 3B6Y) domains of IFI16 at 2.0 and 2.35-Å resolution, respectively. Although IFI16's HIN-A and HIN-B only share ∼40% sequence homology, their structures are very similar. Both domains exhibit α/β folds organized as two subdomains, the first composed of eight β-strands and one α-helix, and the second of six β-strands and one α-helix, forming globular barrels connected via extended α-helical linkers. Both subdomains are homologous to the oligonucleotide/oligosaccharide-binding (OB) fold. The OB folds of each HIN domain interact with each other through conserved residues, and the isolated OB subdomains could not be expressed in a soluble form, suggesting that intersubdomain interactions are important to the overall stability of the HIN domain.

While previous work had implicated IFI16—and possibly the HIN-A domain—in p53 binding, details on the specific interactions and their functional consequences were lacking. Using protein-protein interaction, DNA-binding and p53 transactivation assays, Arrowsmith and colleagues showed that the HIN-A and HIN-B domains interact with different regions of p53. While HIN-A specifically binds the C-terminus, HIN-B interacts solely with the core domain of p53. Each isolated HIN domain enhanced the specific DNA-binding affinity and transcriptional activity of p53. The authors suggest that HIN-A likely functions by preventing nonspecific DNA interactions, a property shared by several p53 C-terminus-binding proteins, whereas HIN-B stabilizes p53-DNA binding to specific sequences.

In addition to its HIN domains, IFI16 possesses an N-terminal PYRIN domain known to interact with another tumor suppressor—BRCA1—that also promotes p53-dependent apoptosis, suggesting a complex interplay between those three factors in tumor suppression. IFI16 can regulate cell proliferation, both in response to and independently from interferon signaling. By defining the molecular details of IFI16 HIN domain-mediated p53 activation, the authors have exposed yet another aspect of the elaborate network that regulates cancer suppression.

Stéphane Larochelle

References

  1. J.C.C. Liao et al. Interferon-inducible protein 16: insight into the interaction with tumor suppressor p53.
    Structure. 19, 418-429 (2011). doi:10.1016/j.str.2010.12.015

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