A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.


Abstract

The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major "hotspot" codons, which account for only ∼30% of cancer-associated p53 mutations. To comprehensively characterize the consequences of the p53 mutation spectrum, we created a synthetically designed library and measured the functional impact of ∼10,000 DNA-binding domain (DBD) p53 variants in human cells in culture and in vivo. Our results highlight the differential outcome of distinct p53 mutations in human patients and elucidate the selective pressure driving p53 conservation throughout evolution. Furthermore, while loss of anti-proliferative functionality largely correlates with the occurrence of cancer-associated p53 mutations, we observe that selective gain-of-function may further favor particular mutants in vivo. Finally, when combined with additional acquired p53 mutations, seemingly neutral TP53 SNPs may modulate phenotypic outcome and, presumably, tumor progression.

Submission Details

ID: axWiFkxq3

Submitter: Connie Wang

Submission Date: July 12, 2018, 11:33 a.m.

Version: 1

Publication Details
Kotler E;Shani O;Goldfeld G;Lotan-Pompan M;Tarcic O;Gershoni A;Hopf TA;Marks DS;Oren M;Segal E,Mol Cell (2018) A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. PMID:29979965
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1DT7 2000-07-26 SOLUTION STRUCTURE OF THE C-TERMINAL NEGATIVE REGULATORY DOMAIN OF P53 IN A COMPLEX WITH CA2+-BOUND S100B(BB)
2J0Z 2007-08-28 p53 tetramerization domain wild type
1PET 1995-02-07 NMR SOLUTION STRUCTURE OF THE TETRAMERIC MINIMUM TRANSFORMING DOMAIN OF P53
2FEJ 2006-01-31 Solution structure of human p53 DNA binding domain.
1HS5 2001-01-10 NMR SOLUTION STRUCTURE OF DESIGNED P53 DIMER
2MWO 2014-12-10 Solution structure of 53BP1 tandem Tudor domains in complex with a p53K370me2 peptide
2MWP 2014-12-10 Solution structure of 53BP1 tandem Tudor domains in complex with a p53K382me2 peptide
5HP0 2016-03-16 Solution Structure of TAZ2-p53AD2
1OLG 1995-01-26 HIGH-RESOLUTION SOLUTION STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR
2J10 2007-08-28 p53 tetramerization domain mutant T329F Q331K
1OLH 1995-03-31 HIGH-RESOLUTION SOLUTION STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR
2MWY 2016-01-27 Mdmx-p53
1SAK 1995-10-15 HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR (SAC STRUCTURES)
2LY4 2012-10-31 HMGB1-facilitated p53 DNA binding occurs via HMG-box/p53 transactivation domain interaction and is regulated by the acidic tail
1JSP 2002-08-17 NMR Structure of CBP Bromodomain in complex with p53 peptide
2L14 2010-11-03 Structure of CBP nuclear coactivator binding domain in complex with p53 TAD
2K8F 2009-03-03 Structural Basis for the Regulation of p53 Function by p300
1A1U 1998-04-08 SOLUTION STRUCTURE DETERMINATION OF A P53 MUTANT DIMERIZATION DOMAIN, NMR, MINIMIZED AVERAGE STRUCTURE
2RUK 2014-10-15 Solution structure of the complex between p53 transactivation domain 2 and TFIIH p62 PH domain
1SAE 1995-10-15 HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR (SAC STRUCTURES)
5HOU 2016-03-16 Solution Structure of p53TAD-TAZ1
1PES 1995-02-07 NMR SOLUTION STRUCTURE OF THE TETRAMERIC MINIMUM TRANSFORMING DOMAIN OF P53
3SAK 1999-06-25 HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR (SAC STRUCTURES)
5HPD 2016-03-16 Solution Structure of TAZ2-p53TAD
2MEJ 2014-04-30 Solution Structure of the Complex Between BCL-xL and the p53 Core Domain determined with PRE restraints
2GS0 2006-10-31 NMR structure of the complex between the PH domain of the Tfb1 subunit from TFIIH and the activation domain of p53
1SAL 1995-10-15 HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR (SAD STRUCTURES)
1SAF 1995-10-15 HIGH RESOLUTION SOLUTION NMR STRUCTURE OF THE OLIGOMERIZATION DOMAIN OF P53 BY MULTI-DIMENSIONAL NMR (SAD STRUCTURES)
2J11 2007-08-28 p53 tetramerization domain mutant Y327S T329G Q331G
2MZD 2015-03-25 Characterization of the p300 Taz2-p53 TAD2 Complex and Comparison with the p300 Taz2-p53 TAD1 Complex
3D06 2009-01-20 1.2 Human p53 core domain with hot spot mutation R249S (I)
5MHC 2017-10-04 1.2 Crystal structure of 14-3-3sigma and a p53 C-terminal 12-mer synthetic phosphopeptide
6GGC 2019-05-22 1.24 p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9320
4MZI 2014-01-15 1.25 Crystal structure of a human mutant p53
6GGE 2019-05-22 1.25 p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9327
3LW1 2010-03-23 1.28 Binary complex of 14-3-3 sigma and p53 pT387-peptide
5O1E 2018-05-09 1.3 p53 cancer mutant Y220C im complex with compound MB577
6GGF 2019-05-22 1.32 Structure of the p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9328
5O1H 2018-05-09 1.32 p53 cancer mutant Y220C in complex with compound MB539
6GGB 2019-05-22 1.32 p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9318
5O1C 2018-05-09 1.32 p53 cancer mutant Y220C in complex with compound MB184
3ZME 2013-05-08 1.35 Structure of the p53 core domain mutant Y220C bound to the small molecule PhiKan7242
5G4N 2016-06-22 1.35 Crystal structure of the p53 cancer mutant Y220C in complex with a difluorinated derivative of the small molecule stabilizer Phikan083
5AOK 2015-12-16 1.35 Structure of the p53 cancer mutant Y220C with bound small molecule PhiKan7099
5O1G 2018-05-09 1.35 p53 cancer mutant Y220C in complex with compound MB487
5AB9 2015-12-16 1.36 Structure of the p53 cancer mutant Y220C with bound small molecule 7- ethyl-3-(piperidin-4-yl)-1H-indole
5O1D 2018-05-09 1.36 p53 cancer mutant Y220C in complex with compound MB481
5O1F 2018-05-09 1.38 p53 cancer mutant Y220C in complex with compound MB582
5G4M 2016-06-22 1.38 Crystal structure of the p53 cancer mutant Y220C in complex with a monofluorinated derivative of the small molecule stabilizer Phikan083
6GGD 2019-05-22 1.4 p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9324
5O1I 2018-05-09 1.4 p53 cancer mutant Y220C in complex with compound MB710
1YC5 2005-04-26 1.4 Sir2-p53 peptide-nicotinamide
5A7B 2015-09-30 1.4 Structure of the p53 cancer Y220C bound to the stabilizing small molecule PhiKan5211
3D08 2009-01-20 1.4 Human p53 core domain with hot spot mutation R249S and second-site suppressor mutation H168R
4AGQ 2012-03-21 1.42 Structure of the p53 core domain mutant Y220C bound to the stabilizing small molecule PhiKan5196
5LAP 2016-08-10 1.42 p53 cancer mutant Y220C with Cys182 alkylation
5O1B 2018-05-09 1.43 p53 cancer mutant Y220C in complex with compound MB84
5O1A 2018-05-09 1.44 p53 cancer mutant Y220C in complex with compound MB240
4AGO 2012-03-21 1.45 Structure of the p53 core domain mutant Y220C bound to the stabilizing small molecule PhiKan5174
4IBY 2013-08-14 1.45 Human p53 core domain with hot spot mutation R273H and second-site suppressor mutation S240R
5MCT 2018-06-13 1.45 New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins (complex p53DBD-LHG1)
5MG7 2018-06-13 1.45 New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins (complex p53DBD-p53R2)
5AOJ 2015-12-16 1.47 Structure of the p53 cancer mutant Y220C in complex with 2-hydroxy-3, 5-diiodo-4-(1H-pyrrol-1-yl)benzoic acid
5G4O 2016-06-22 1.48 Crystal structure of the p53 cancer mutant Y220C in complex with a trifluorinated derivative of the small molecule stabilizer Phikan083
4KVP 2013-07-31 1.5 Human p53 Core Domain Mutant V157F
4AGP 2012-03-21 1.5 Structure of the p53 core domain mutant Y220C bound to the stabilizing small molecule PhiKan5176
5AOL 2015-12-16 1.5 Structure of the p53 cancer mutant Y220C with bound 3-bromo-5-(trifluoromethyl)benzene-1,2-diamine
2VUK 2008-07-22 1.5 Structure of the p53 core domain mutant Y220C bound to the stabilizing small-molecule drug PhiKan083
1AIE 1997-06-16 1.5 P53 TETRAMERIZATION DOMAIN CRYSTAL STRUCTURE
4AGM 2012-03-21 1.52 Structure of the p53 core domain mutant Y220C bound to the stabilizing small molecule PhiKan5086
2PCX 2008-04-08 1.54 Crystal structure of p53DBD(R282Q) at 1.54-angstrom Resolution
6GGA 2019-05-22 1.55 p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9284
4RP7 2016-01-13 1.58 Structure of the amyloid-forming segment TIITLE from p53 (residues 253-258)
5MF7 2018-05-30 1.59 New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins (complex p53DBD-GADD45)
2B3G 2005-10-11 1.6 p53N (fragment 33-60) bound to RPA70N
2X0U 2010-01-26 1.6 STRUCTURE OF THE P53 CORE DOMAIN MUTANT Y220C BOUND TO A 2-amino substituted benzothiazole scaffold
2J21 2006-09-20 1.6 Human p53 core domain mutant M133L-V203A-N239Y-N268D-R282W
4AGN 2012-03-21 1.6 Structure of the p53 core domain mutant Y220C bound to the stabilizing small molecule PhiKan5116
2FOJ 2006-02-14 1.6 The Crystal Structure of the N-terminal domain of HAUSP/USP7 complexed with p53 peptide 364-367
5MCV 2018-06-13 1.6 New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins (complex p53DBD-LWC1)
5ABA 2015-12-16 1.62 Structure of the p53 cancer mutant Y220C with bound small-molecule stabilizer PhiKan5149
2J1X 2006-09-20 1.65 Human p53 core domain mutant M133L-V203A-Y220C-N239Y-N268D
2XWR 2011-03-30 1.68 Crystal structure of the DNA-binding domain of human p53 with extended N terminus
2J1Y 2006-09-20 1.69 Human p53 core domain mutant M133L-V203A-N239Y-G245S-N268D
4IBT 2013-08-14 1.7 Human p53 core domain with hot spot mutation R273H and second-site suppressor mutation T284R
4AGL 2012-03-21 1.7 Structure of the p53 core domain mutant Y220C bound to the stabilizing small molecule PhiKan784
2H2D 2006-09-19 1.7 The Structural Basis for Sirtuin Substrate Affinity
5MCU 2018-06-13 1.7 New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins (complex p53DBD-LHG2)
3IGK 2010-03-31 1.7 Diversity in DNA recognition by p53 revealed by crystal structures with Hoogsteen base pairs (p53-DNA complex 2)
4IBU 2013-08-14 1.7 Human p53 core domain with hot spot mutation R273C and second-site suppressor mutation T284R in sequence-specific complex with DNA
4RP6 2016-01-13 1.7 Structure of the amyloid-forming segment LTIITLE from p53 (residues 252-258)
1C26 1999-07-27 1.7 CRYSTAL STRUCTURE OF P53 TETRAMERIZATION DOMAIN
3D05 2009-01-20 1.7 Human p53 core domain with hot spot mutation R249S (II)
5AOM 2015-12-16 1.74 Structure of the p53 cancer mutant Y220C with bound small molecule PhiKan883
2WGX 2009-05-12 1.75 HUMAN P53 CORE DOMAIN MUTANT M133L-V203A-Y236F-N239Y-T253I-N268D
1XQH 2004-11-23 1.75 Crystal structure of a ternary complex of the methyltransferase SET9 (also known as SET7/9) with a P53 peptide and SAH
4IBS 2013-08-14 1.78 Human p53 core domain with hot spot mutation R273H (form I)
5AOI 2015-12-16 1.78 Structure of the p53 cancer mutant Y220C in complex with an indole- based small molecule
4IJT 2013-08-14 1.78 Human p53 core domain with hot spot mutation R273H (form II)
4IBW 2013-08-14 1.79 Human p53 core domain with hot spot mutation R273H and second-site suppressor mutation T284R in sequence-specific complex with DNA
4IBQ 2013-08-14 1.8 Human p53 core domain with hot spot mutation R273C
2J1W 2006-09-20 1.8 Human p53 core domain mutant M133L-V143A-V203A-N239Y-N268D
3DAC 2008-09-02 1.8 Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain
2BIQ 2005-01-26 1.8 human p53 core domain mutant T123A-M133L-H168R-V203A-N239Y-R249S- N268D
3PDH 2011-01-19 1.8 Structure of Sir2Tm bound to a propionylated peptide
4X34 2015-03-04 1.8 Crystal structure of the 53BP1 tandem tudor domain in complex with p53K381acK382me2
2J1Z 2006-09-20 1.8 Human p53 core domain mutant M133L-V203A-N239Y-N268D-F270L
2BIP 2005-01-26 1.8 human p53 core domain mutant M133L-H168R-V203A-N239Y-R249S-N268D
2J20 2006-09-20 1.8 Human p53 core domain mutant M133L-V203A-N239Y-N268D-R273C
2AC0 2006-07-11 1.8 Structural Basis of DNA Recognition by p53 Tetramers (complex I)
3D0A 2009-01-20 1.8 Human p53 core domain with hot spot mutation R249S and second site suppressor mutation H168R in sequence-specific complex with DNA
2X0V 2010-01-26 1.8 STRUCTURE OF THE P53 CORE DOMAIN MUTANT Y220C BOUND TO 4-(trifluoromethyl)benzene-1,2-diamine
5MOC 2017-10-04 1.8 Crystal structure of 14-3-3sigma and a p53 C-terminal 12-mer synthetic phosphopeptide
3IGL 2010-03-31 1.8 Diversity in DNA recognition by p53 revealed by crystal structures with Hoogsteen base pairs (p53-DNA complex 1)
5BUA 2016-07-06 1.81 Lysine 120-acetylated P53 DNA binding domain in a complex with DNA.
2AHI 2006-07-11 1.85 Structural Basis of DNA Recognition by p53 Tetramers (complex III)
4LOE 2013-07-31 1.85 Human p53 Core Domain Mutant N239Y
3DAB 2008-09-02 1.9 Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain
5MCW 2018-06-13 1.9 New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins (complex p53DBD-LWC2)
4BUZ 2013-07-17 1.9 SIR2 COMPLEX STRUCTURE MIXTURE OF EX-527 INHIBITOR AND REACTION PRODUCTS OR OF REACTION SUBSTRATES P53 PEPTIDE AND NAD
3D09 2009-01-20 1.9 Human p53 core domain with hot spot mutation R249S and second-site suppressor mutations H168R and T123A
2H59 2006-09-05 1.9 Sir2 H116A-deacetylated p53 peptide-3'-o-acetyl ADP ribose
2YBG 2011-05-04 1.9 Structure of Lys120-acetylated p53 core domain
2BIN 2005-01-26 1.9 human p53 core domain mutant M133L-H168R-V203A-N239Y-N268D
1UOL 2003-10-16 1.9 Crystal structure of the human p53 core domain mutant M133L/V203A/N239Y/N268D at 1.9 A resolution.
2BIO 2005-01-26 1.9 human p53 core domain mutant M133L-V203A-N239Y-R249S-N268D
3KZ8 2010-03-31 1.91 Diversity in DNA recognition by p53 revealed by crystal structures with Hoogsteen base pairs (p53-DNA complex 3)
4HJE 2013-07-17 1.91 Crystal structure of p53 core domain in complex with DNA
4IBZ 2013-08-14 1.92 Human p53 core domain with hot spot mutation R273C and second-site suppressor mutation T284R
4QO1 2014-10-29 1.92 p53 DNA binding domain in complex with Nb139
2BIM 2005-01-26 1.98 human p53 core domain mutant M133L-V203A-N239Y-N268D-R273H
5OL0 2018-02-28 1.99 Structure of Leishmania infantum Silent Information Regulator 2 related protein 1 (LiSIR2rp1) in complex with acetylated p53 peptide
2H4H 2006-09-05 1.99 Sir2 H116Y mutant-p53 peptide-NAD
5XZC 2019-01-23 10.7 Cryo-EM structure of p300-p53 protein complex
1MA3 2002-10-16 2.0 Structure of a Sir2 enzyme bound to an acetylated p53 peptide
2V5W 2007-09-04 2.0 Crystal structure of HDAC8-substrate complex
6FF9 2018-04-25 2.0 Mutant R280K of human P53
4LOF 2013-07-31 2.0 Human p53 Core Domain Mutant V157F/N235K/N239Y
2H4F 2006-09-05 2.0 Sir2-p53 peptide-NAD+
6FJ5 2018-06-27 2.05 New Insights into the Role of DNA Shape on Its Recognition by p53 Proteins (complex p53DBD-AGG-HG)
2OCJ 2007-03-06 2.05 Human p53 core domain in the absence of DNA
3Q01 2011-05-11 2.1 An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity
2H4J 2006-09-05 2.1 Sir2-deacetylated peptide (from enzymatic turnover in crystal)
4FZ3 2013-03-20 2.1 Crystal structure of SIRT3 in complex with acetyl p53 peptide coupled with 4-amino-7-methylcoumarin
4IBV 2013-08-14 2.1 Human p53 core domain with hot spot mutation R273C and second-site suppressor mutation S240R in sequence-specific complex with DNA
2X0W 2010-01-26 2.1 STRUCTURE OF THE P53 CORE DOMAIN MUTANT Y220C BOUND TO 5,6-dimethoxy- 2-methylbenzothiazole
5UN8 2017-03-15 2.13 Crystal Structure of human O-GlcNAcase in complex with glycopeptide p53
3KMD 2010-02-23 2.15 Crystal structure of the p53 core domain bound to a full consensus site as a self-assembled tetramer
2FOO 2006-02-14 2.2 The Crystal Structure of the N-terminal domain of HAUSP/USP7 complexed with p53 peptide 359-362
2H2F 2006-12-05 2.2 The Structural basis for Sirtuin Substrate affinity
1TSR 1996-01-29 2.2 P53 CORE DOMAIN IN COMPLEX WITH DNA
2ATA 2006-07-11 2.2 Structural Basis of DNA Recognition by p53 Tetramers (complex II)
3D07 2009-01-20 2.2 Human p53 core domain with hot spot mutation R249S (III)
1YCS 1997-11-19 2.2 P53-53BP2 COMPLEX
1TUP 1995-07-11 2.2 TUMOR SUPPRESSOR P53 COMPLEXED WITH DNA
1H26 2003-02-01 2.24 CDK2/CyclinA in complex with an 11-residue recruitment peptide from p53
4XR8 2016-02-03 2.25 Crystal structure of the HPV16 E6/E6AP/p53 ternary complex at 2.25 A resolution
2Z5S 2007-11-06 2.3 Molecular basis for the inhibition of p53 by Mdmx
1YCQ 1997-11-19 2.3 XENOPUS LAEVIS MDM2 BOUND TO THE TRANSACTIVATION DOMAIN OF HUMAN P53
3TG5 2011-08-31 2.3 Structure of SMYD2 in complex with p53 and SAH
2Z5T 2007-11-06 2.3 Molecular basis for the inhibition of p53 by Mdmx
3Q05 2011-05-11 2.4 An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity
4LO9 2013-07-31 2.5 Human p53 Core Domain Mutant N235K
1KZY 2002-03-20 2.5 Crystal Structure of the 53bp1 BRCT Region Complexed to Tumor Suppressor P53
2ADY 2006-07-11 2.5 Structural Basis of DNA Recognition by p53 Tetramers (complex IV)
3OQ5 2010-09-22 2.5 Crystal structure of the 3-MBT domain from human L3MBTL1 in complex with p53K382me1
1GZH 2002-06-27 2.6 Crystal structure of the BRCT domains of human 53BP1 bound to the p53 tumor supressor
1YCR 1997-11-19 2.6 MDM2 BOUND TO THE TRANSACTIVATION DOMAIN OF P53
4HFZ 2013-07-31 2.69 Crystal Structure of an MDM2/P53 Peptide Complex
4ZZJ 2015-07-15 2.74 SIRT1/Activator/Substrate Complex
2YDR 2012-03-14 2.75 CpOGA D298N in complex with p53-derived O-GlcNAc peptide
3TS8 2011-11-23 2.8 Crystal structure of a multidomain human p53 tetramer bound to the natural CDKN1A(p21) p53-response element
4MZR 2014-01-15 2.9 Crystal structure of a polypeptide p53 mutant bound to DNA
5LGY 2016-07-27 2.92 Lysine 120-acetylated P53 DNA binding domain in a complex with the BAX response element.
5ECG 2015-12-16 3.0 Crystal structure of the BRCT domains of 53BP1 in complex with p53 and H2AX-pSer139 (gammaH2AX)
2H1L 2006-09-12 3.16 The Structure of the Oncoprotein SV40 Large T Antigen and p53 Tumor Suppressor Complex
3Q06 2011-05-11 3.2 An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity
4BV2 2013-07-17 3.3 CRYSTAL STRUCTURE OF SIR2 IN COMPLEX WITH THE INHIBITOR EX-527, 2'-O-ACETYL-ADP-RIBOSE AND DEACETYLATED P53-PEPTIDE

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
93.1 Cellular tumor antigen p53 Q9TTA1 P53_TUPBE
95.7 Cellular tumor antigen p53 P56424 P53_MACMU
95.7 Cellular tumor antigen p53 P61260 P53_MACFU
95.7 Cellular tumor antigen p53 P56423 P53_MACFA
95.2 Cellular tumor antigen p53 P13481 P53_CHLAE
100.0 Cellular tumor antigen p53 P04637 P53_HUMAN