Disorder and residual helicity alter p53-Mdm2 binding affinity and signaling in cells

被引：145

作者：

Borcherds, Wade ^{[1
,2
]}

Theillet, Francois-Xavier ^{[3
]}

Katzer, Andrea ^{[4
]}

Finzel, Ana ^{[4
]}

Mishall, Katie M. ^{[1
,2
]}

Powell, Anne T. ^{[1
,2
]}

Wu, Hongwei ^{[1
,2
]}

Manieri, Wanda ^{[5
]}

Dieterich, Christoph ^{[6
]}

Selenko, Philipp ^{[3
]}

Loewer, Alexander ^{[4
]}

Daughdrill, Gary W. ^{[1
,2
]}

机构：

[1] Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA

[2] Univ S Florida, Ctr Drug Discovery & Innovat, Tampa, FL USA

[3] Leibniz Inst Mol Pharmacol FMP Berlin, Dept NMR Supported Struct Biol, In Cell NMR Lab, Berlin, Germany

[4] Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Berlin, Germany

[5] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Dept, Tampa, FL 33682 USA

[6] Max Planck Inst Biol Ageing, Cologne, Germany

来源：

NATURE CHEMICAL BIOLOGY | 2014年 / 10卷 / 12期

基金：

美国国家科学基金会;

关键词：

TUMOR-SUPPRESSOR P53; TRANSACTIVATION DOMAIN; ACTIVATION; DYNAMICS; PROTEIN; MDM2; EXPRESSION; LANDSCAPE; SYSTEM; PULSES;

D O I：

10.1038/nchembio.1668

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Levels of residual structure in disordered interaction domains determine in vitro binding affinities, but whether they exert similar roles in cells is not known. Here, we show that increasing residual p53 helicity results in stronger Mdm2 binding, altered p53 dynamics, impaired target gene expression and failure to induce cell cycle arrest upon DNA damage. These results establish that residual structure is an important determinant of signaling fidelity in cells.

引用

页码：1000 / +

页数：5

共 31 条

[1] Recurrent initiation: A mechanism for triggering p53 pulses in response to DNA damage [J].

Batchelor, Eric ;

Mock, Caroline S. ;

Bhan, Irun ;

Loewer, Alexander ;

Lahav, Galit .

MOLECULAR CELL, 2008, 30 (03) :277-289

[2] A system for stable expression of short interfering RNAs in mammalian cells [J].

Brummelkamp, TR ;

Bernards, R ;

Agami, R .

SCIENCE, 2002, 296 (5567) :550-553

[3] Energetic Basis of Uncoupling Folding from Binding for an Intrinsically Disordered Protein [J].

Drobnak, Igor ;

De Jonge, Natalie ;

Haesaerts, Sarah ;

Vesnaver, Gorazd ;

Loris, Remy ;

Lah, Jurij .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135 (04) :1288-1294

[4] A third-generation lentivirus vector with a conditional packaging system [J].

Dull, T ;

Zufferey, R ;

Kelly, M ;

Mandel, RJ ;

Nguyen, M ;

Trono, D ;

Naldini, L .

JOURNAL OF VIROLOGY, 1998, 72 (11) :8463-8471

[5] Conformational entropy in molecular recognition by proteins [J].

Frederick, Kendra King ;

Marlow, Michael S. ;

Valentine, Kathleen G. ;

Wand, A. Joshua .

NATURE, 2007, 448 (7151) :325-U3

[6] Activation and control of p53 tetramerization in individual living cells [J].

Gaglia, Giorgio ;

Guan, Yinghua ;

Shah, Jagesh V. ;

Lahav, Galit .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (38) :15497-15501

[7] Helical Propensity in an Intrinsically Disordered Protein Accelerates Ligand Binding [J].

Iesmantavicius, Vytautas ;

Dogan, Jakob ;

Jemth, Per ;

Teilum, Kaare ;

Kjaergaard, Magnus .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2014, 53 (06) :1548-1551

[8] NMR VIEW - A COMPUTER-PROGRAM FOR THE VISUALIZATION AND ANALYSIS OF NMR DATA [J].

JOHNSON, BA ;

BLEVINS, RA .

JOURNAL OF BIOMOLECULAR NMR, 1994, 4 (05) :603-614

[9] Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain [J].

Kussie, PH ;

Gorina, S ;

Marechal, V ;

Elenbaas, B ;

Moreau, J ;

Levine, AJ ;

Pavletich, NP .

SCIENCE, 1996, 274 (5289) :948-953

[10] Dynamics of the p53-Mdm2 feedback loop in individual cells [J].

Lahav, G ;

Rosenfeld, N ;

Sigal, A ;

Geva-Zatorsky, N ;

Levine, AJ ;

Elowitz, MB ;

Alon, U .

NATURE GENETICS, 2004, 36 (02) :147-150

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