The conformationally flexible S9-S10 linker region in the core domain of p53 contains a novel MDM2 binding site whose mutation increases ubiquitination of p53 in vivo

The Journal of Biological Chemistry
Harumi ShimizuTed Hupp

Abstract

Although the N-terminal BOX-I domain of the tumor suppressor protein p53 contains the primary docking site for MDM2, previous studies demonstrated that RNA stabilizes the MDM2.p53 complex using a p53 mutant lacking the BOX-I motif. In vitro assays measuring the specific activity of MDM2 in the ligand-free and RNA-bound state identified a novel MDM2 interaction site in the core domain of p53. As defined using phage-peptide display, the RNA.MDM2 isoform exhibited a notable switch in peptide binding specificity, with enhanced affinity for novel peptide sequences in either p53 or small nuclear ribonucleoprotein-U (snRNP-U) and substantially reduced affinity for the primary p53 binding site in the BOX-I domain. The consensus binding site for the RNA.MDM2 complex within p53 is SGXLLGESXF, which links the S9-S10 beta-sheets flanking the BOX-IV and BOX-V motifs in the core domain and which is a site of reversible conformational flexibility in p53. Mutation of conserved amino acids in the linker at Ser(261) and Leu(264), which bridges the S9-S10 beta-sheets, stimulated p53 activity from reporter templates and increased MDM2-dependent ubiquitination of p53. Furthermore, mutation of the conserved Phe(270) within the S10 beta-sheet resulte...Continue Reading

References

Mar 15, 1979·Nature·D P Lane, L V Crawford
Oct 1, 1994·Current Biology : CB·T R Hupp, D P Lane
Jun 1, 1994·Current Opinion in Cell Biology·U Scheer, D Weisenberger
Jun 21, 1994·Proceedings of the National Academy of Sciences of the United States of America·K IwabuchiS Fields
Jul 1, 1993·Genes & Development·X WuA J Levine
Oct 11, 1996·The Journal of Biological Chemistry·P FriedlanderC Prives
Jan 1, 1997·Molecular and Cellular Biology·C G Maki, P M Howley
May 15, 1997·Nature·Y HauptM Oren
Aug 1, 1997·Genes & Development·C J ThutR Tjian
Jan 10, 1998·The Journal of Biological Chemistry·T Léveillard, B Wasylyk
Sep 23, 1998·Genes & Development·K SakaguchiE Appella
Nov 21, 1998·Oncogene·S Y FuchsZ Ronai
Dec 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·P V NikolovaA R Fersht
Mar 5, 1999·Cellular and Molecular Life Sciences : CMLS·L Jayaraman, C Prives
May 29, 1999·The Journal of Biological Chemistry·C G Maki
Sep 17, 1999·The Journal of Biological Chemistry·D P Xirodimas, D P Lane
Dec 14, 1999·The Journal of Biological Chemistry·M Oren
Jan 5, 2000·Science·B A FosterF Rastinejad
Jan 15, 2000·Mutation Research·M HollsteinP Hainaut
Feb 25, 2000·Molecular and Cellular Biology·O Loughran, N B La Thangue
Jul 8, 2000·Journal of Molecular Biology·M G LucianiT R Hupp
Oct 29, 2000·The Journal of Biological Chemistry·M BergerY Haupt
Nov 18, 2000·The Journal of Biological Chemistry·J P BlaydesT R Hupp

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Citations

Nov 8, 2008·Molecular Biotechnology·Andrej SavchenkoElena Kashuba
Jul 2, 2009·Journal of Chemical Biology·Erin G WorrallTed R Hupp
Sep 23, 2003·Journal of Molecular Biology·Roger DawsonJohannes Buchner
Jan 27, 2004·Journal of Molecular Biology·Oliver SchonAlan R Fersht
Jul 25, 2003·Trends in Biochemical Sciences·Harumi Shimizu, Ted R Hupp
Sep 5, 2009·Nature Reviews. Cancer·David W Meek
Jul 20, 2010·Nature Structural & Molecular Biology·Masha V PoyurovskyCarol Prives
Mar 18, 2006·Cell Death and Differentiation·K L Harms, X Chen
Jan 24, 2007·Oncogene·N Allende-VegaD W Meek
Feb 23, 2010·Proceedings of the National Academy of Sciences of the United States of America·Xiaoyong FuYi Wang
Apr 2, 2011·The Journal of Biological Chemistry·Brittany CrossJiandong Chen
Feb 4, 2009·The Journal of Biological Chemistry·Bartosz WawrzynowKathryn L Ball
Feb 4, 2012·Carcinogenesis·Patricia RoxburghKaren H Vousden
Oct 19, 2010·Protein Engineering, Design & Selection : PEDS·Maria Rosario Fernandez-Fernandez, Begoña Sot
May 14, 2010·Cold Spring Harbor Perspectives in Biology·David P LaneSonia Lain
May 17, 2008·Genes & Development·Carol Prives, Eileen White
Oct 3, 2007·Molecular and Cellular Biology·Natalia Lukashchuk, Karen H Vousden
Jul 2, 2003·Molecular and Cellular Biology·Erik MeulmeesterAart G Jochemsen
Jul 2, 2003·Molecular and Cellular Biology·Hidehiko KawaiZhi-Min Yuan
Nov 15, 2012·Genes & Cancer·Anand PonnuswamyRobin Fåhraeus
Nov 15, 2012·Genes & Cancer·Ian M Love, Steven R Grossman
Sep 1, 2009·Future Medicinal Chemistry·Christiane Riedinger, James M McDonnell
Jan 25, 2006·Proceedings of the National Academy of Sciences of the United States of America·Grace W YuAlan R Fersht
Feb 13, 2013·Molecular Pharmaceutics·James R DavisCarol S Lim
Jan 7, 2016·Frontiers in Oncology·Reshma VijayakumaranYgal Haupt
Jul 27, 2010·Trends in Cell Biology·Magda M Maslon, Ted R Hupp
Nov 10, 2009·Seminars in Cancer Biology·Nerea Allende-Vega, Mark K Saville
Apr 9, 2009·Biochemical and Biophysical Research Communications·Fredrik M Berglund, Paul R Clarke
Dec 17, 2008·Experimental Cell Research·Elisabeth HedströmGalina Selivanova
Aug 30, 2008·The FEBS Journal·Craig StevensTed R Hupp
May 29, 2015·Journal of Cellular Biochemistry·Elizabeth ChippsM Rafiq Islam

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