iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- Ludwig Institute for Cancer Research Ltd., Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- University of Oxford
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242.
- Department of Biostatistics, University of Iowa, Iowa City, IA 52242.
The most frequently mutated protein in human cancer is p53, a transcription factor (TF) that regulates myriad genes instrumental in diverse cellular outcomes including growth arrest and cell death. Cell context-dependent p53 modulation is critical for this life-or-death balance, yet remains incompletely understood. Here we identify sequence signatures enriched in genomic p53-binding sites modulated by the transcription cofactor iASPP. Moreover, our p53-iASPP crystal structure reveals that iASPP displaces the p53 L1 loop-which mediates sequence-specific interactions with the signature-corresponding base-without perturbing other DNA-recognizing modules of the p53 DNA-binding domain. A TF commonly uses multiple structural modules to recognize its cognate DNA, and thus this mechanism of a cofactor fine-tuning TF-DNA interactions through targeting a particular module is likely widespread. Previously, all tumor suppressors and oncoproteins that associate with the p53 DNA-binding domain-except the oncogenic E6 from human papillomaviruses (HPVs)-structurally cluster at the DNA-binding site of p53, complicating drug design. By contrast, iASPP inhibits p53 through a distinct surface overlapping the E6 footprint, opening prospects for p53-targeting precision medicine to improve cancer therapy.
|Number of pages||10|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Early online date||8 Aug 2019|
|Publication status||Published - 27 Aug 2019|