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

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.

• Authors: Shuo Chen, Jiale Wu, Shan Zhong, Yuntong Li, Ping Zhang, Jingyi Ma, Jingshan Ren, Yun Tan, Yunhao Wang, Kin Fai Au, Christian Siebold, Gareth L Bond, Zhu Chen, Min Lu, E Yvonne Jones, Xin Lu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 35 Pg. 17470-17479 (08 27 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31395738 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Oncogene Proteins, Viral
• PPP1R13L protein, human
• Repressor Proteins
• Tumor Suppressor Protein p53
• DNA

Topics

• Base Sequence
• Binding Sites
• Cell Line, Tumor
• DNA (chemistry, genetics, metabolism)
• Gene Expression Profiling
• Humans
• Intracellular Signaling Peptides and Proteins (chemistry, metabolism)
• Models, Molecular
• Nucleotide Motifs
• Oncogene Proteins, Viral (chemistry, metabolism)
• Protein Binding
• Protein Conformation
• Repressor Proteins (chemistry, metabolism)
• Response Elements
• Structure-Activity Relationship
• Tumor Suppressor Protein p53 (chemistry, metabolism)