PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Design and Evolution: Molecular Sleuthing Reveals Drug Selectivity
June 2015
Families in Gene Neighborhoods
June 2015
Ryanodine Receptor
April 2015
CCR5 and HIV Infection
January 2015
Drug Targets: Bile Acids in Motion
September 2014
Drug Targets: S1R's Ligands and Partners
September 2014
P2Y Receptors and Blood Clotting
September 2014
Bacterial CDI Toxins
June 2014
Glucagon Receptor
April 2014
March 2014
Microbial Pathogenesis: Targeting Drug Resistance in Mycobacterium tuberculosis
February 2014
Design and Discovery: Virtual Drug Screening
January 2014
Cancer Networks: IFI16-mediated p53 Activation
November 2013
G Proteins and Cancer
November 2013
Drug Discovery: Antidepressant Potential of 6-NQ SERT Inhibitors
October 2013
Drug Discovery: Finding Druggable Targets
October 2013
Drug Discovery: Identifying Dynamic Networks by CONTACT
October 2013
Drug Discovery: Modeling NET Interactions
October 2013
Membrane Proteome: GPCR Substrate Recognition and Functional Selectivity
August 2013
Infectious Diseases: Determining the Essential Structome
May 2013
NDM-1 and Antibiotics
May 2013
Microbial Pathogenesis: Computational Epitope Prediction
January 2013
Microbial Pathogenesis: Influenza Inhibitor Screen
January 2013
Microbial Pathogenesis: Measles Virus Attachment
January 2013
Cytochrome Oxidase
November 2012
Membrane Proteome: The ABCs of Transport
November 2012
Bacterial Phosphotransferase System
October 2012
Regulatory insights
September 2012
Solute Channels
September 2012
Pocket changes
July 2012
Receptor bias
July 2012
Anthrax Stealth Siderophores
June 2012
G Protein-Coupled Receptors
May 2012
Substrate specificity sleuths
April 2012
Reading out regioselectivity
December 2011
Superbugs and Antibiotic Resistance
December 2011
Terminal activation
December 2011
A change to resistance
November 2011
Docking and rolling
October 2011
Breaking down the defenses
September 2011
A2A Adenosine Receptor
May 2011
Cell wall recycler
May 2011
Subtly different
March 2011
January 2011
Subtle shifts
January 2011
ABA receptor diversity
November 2010
COX inhibition: Naproxen by proxy
November 2010
Zinc Transporter ZntB
July 2010
Peptidoglycan binding: Calcium-free killing
June 2010
Treating sleeping sickness
May 2010
Bacterial spore kinase
April 2010
Antibiotics and Ribosome Function
March 2010
Safer Alzheimer's drugs?
March 2010
Anthrax evasion tactics
September 2009
GPCR subunits: Separate but not equal
September 2009
Antibiotic target
August 2009
Salicylic Acid Binding Protein 2
August 2009
July 2009
Tackling influenza
June 2009
Bacterial Leucine Transporter, LeuT
May 2009
Anthrax stealth molecule
March 2009
Drug targets to aim for
February 2009
High-energy storage system
February 2009
Transporter mechanism in sight
February 2009
Scavenger Decapping Enzyme DcpS
November 2008
Blocking AmtB
September 2008

Research Themes Drug discovery

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


  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

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health