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iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition

DOI: 10.1073/pnas.1909393116 DOI Help

Authors: Shuo Chen (University of Oxford) , Jiale Wu (Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine) , Shan Zhong (University of Oxford) , Yuntong Li (Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine) , Ping Zhang (University of Oxford) , Jingyi Ma (University of Oxford) , Jingshan Ren (University of Oxford) , Yun Tan (Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine) , Yunhao Wang (University of Iowa) , Kin Fai Au (University of Iowa) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford) , Gareth L. Bond (University of Oxford) , Zhu Chen (Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine) , Min Lu (Rui Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine) , E. Yvonne Jones (Wellcome Centre for Human Genetics, University of Oxford) , Xin Lu (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 175

State: Published (Approved)
Published: August 2019

Open Access Open Access

Abstract: 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.

Journal Keywords: p53; iASPP; crystal structure; target selectivity; HPV E6

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

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