Cargando…

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

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 incomple...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Shuo, Wu, Jiale, Zhong, Shan, Li, Yuntong, Zhang, Ping, Ma, Jingyi, Ren, Jingshan, Tan, Yun, Wang, Yunhao, Au, Kin Fai, Siebold, Christian, Bond, Gareth L., Chen, Zhu, Lu, Min, Jones, E. Yvonne, Lu, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717262/
https://www.ncbi.nlm.nih.gov/pubmed/31395738
http://dx.doi.org/10.1073/pnas.1909393116
_version_ 1783447526464028672
author Chen, Shuo
Wu, Jiale
Zhong, Shan
Li, Yuntong
Zhang, Ping
Ma, Jingyi
Ren, Jingshan
Tan, Yun
Wang, Yunhao
Au, Kin Fai
Siebold, Christian
Bond, Gareth L.
Chen, Zhu
Lu, Min
Jones, E. Yvonne
Lu, Xin
author_facet Chen, Shuo
Wu, Jiale
Zhong, Shan
Li, Yuntong
Zhang, Ping
Ma, Jingyi
Ren, Jingshan
Tan, Yun
Wang, Yunhao
Au, Kin Fai
Siebold, Christian
Bond, Gareth L.
Chen, Zhu
Lu, Min
Jones, E. Yvonne
Lu, Xin
author_sort Chen, Shuo
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6717262
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-67172622019-09-13 iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition Chen, Shuo Wu, Jiale Zhong, Shan Li, Yuntong Zhang, Ping Ma, Jingyi Ren, Jingshan Tan, Yun Wang, Yunhao Au, Kin Fai Siebold, Christian Bond, Gareth L. Chen, Zhu Lu, Min Jones, E. Yvonne Lu, Xin Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2019-08-27 2019-08-08 /pmc/articles/PMC6717262/ /pubmed/31395738 http://dx.doi.org/10.1073/pnas.1909393116 Text en Copyright © 2019 the Author(s). Published by PNAS. http://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle PNAS Plus
Chen, Shuo
Wu, Jiale
Zhong, Shan
Li, Yuntong
Zhang, Ping
Ma, Jingyi
Ren, Jingshan
Tan, Yun
Wang, Yunhao
Au, Kin Fai
Siebold, Christian
Bond, Gareth L.
Chen, Zhu
Lu, Min
Jones, E. Yvonne
Lu, Xin
iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
title iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
title_full iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
title_fullStr iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
title_full_unstemmed iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
title_short iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition
title_sort iaspp mediates p53 selectivity through a modular mechanism fine-tuning dna recognition
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717262/
https://www.ncbi.nlm.nih.gov/pubmed/31395738
http://dx.doi.org/10.1073/pnas.1909393116
work_keys_str_mv AT chenshuo iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT wujiale iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT zhongshan iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT liyuntong iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT zhangping iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT majingyi iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT renjingshan iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT tanyun iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT wangyunhao iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT aukinfai iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT sieboldchristian iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT bondgarethl iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT chenzhu iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT lumin iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT joneseyvonne iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition
AT luxin iasppmediatesp53selectivitythroughamodularmechanismfinetuningdnarecognition