Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs
Abstract
:1. Introduction
2. Results
2.1. Sequence Features of Phosphorylation Sites in p53
2.1.1. Consensus Motifs within the Phosphorylation Sites in p53
P−3 | P−2 | P−1 | pS/pT | P+1 | P+2 | P+3 | Kinases | Consensus Motif | Ref. |
---|---|---|---|---|---|---|---|---|---|
E | P | Q | S6 | D | P | S | JNK2, CK1δ | P-X-S/T-P | [6,7] |
S | D | P | S9 | V | E | P | CK1ε | pS-X-X-S/T | [6,7] |
P | P | L | S15 | Q | E | T | CDK5, mTOR, ATM | P-L-S/T-P (CDK) D-S/T-Q-E (ATM)D | [14,15] |
S | Q | E | T18 | F | S | D | Chk2, TTK, VRK1 | [14,15] | |
E | T | F | S20 | D | L | W | Chk2, Plk3 | T-X-S/T-X-X-W (Chk2) | [14,15] |
N | V | L | S33 | P | L | P | Cdk5/7/9, GSK3β, p38K | P-L-S/T-P (CDK) | [6,7] |
P | L | P | S37 | Q | A | M | ATR, PRAK | L-P-S/T-Q-A (ATR) | [6,7] |
L | M | L | S46 | P | D | D | Cdk5, p38K, PKC | P-L-S/T-P (CDK) | [20] |
Q | W | F | T55 | E | D | P | ERK2, TAF1 | [21] | |
A | A | P | T81 | P | A | A | JNK2 | P-X-S/T-P | [6,7] |
S | V | P | S99 | Q | K | T | ATM, ATR | V-P-S/T-Q (ATR) | [6,7] |
Y | Q | G | S106 | Y | G | F | Aurora A | [6,7] | |
N | N | T | S313 | S | S | P | Chk1/2 | [6,7] | |
N | T | S | S314 | S | P | Q | Chk1/2 | T-X-S/T (Chk2) | [6,7] |
T | S | S | S315 | P | Q | P | STK15, Cdk9, CDK2 | P-L-S/T-P (CDK) | [24,25] |
P | G | G | S362 | R | A | H | IKK2B | [6,7] | |
R | A | H | S366 | S | H | L | IKK2, Chk2 | [6,7] | |
K | G | Q | S376 | T | S | R | PKC, GSK3β | R-K/R-X-S/T-X-K-K/R (PKC) | [25,26] |
G | Q | S | T377 | S | R | H | Chk1/2 | [6,7] | |
Q | S | T | S378 | R | H | K | Chk1/2, PKC | R-K/R-X-S/T-X-K-K/R (PKC) | [6,7] |
M | F | K | T387 | E | G | P | Chk1 | [6,7] | |
G | P | D | S392 | D | Cdk9, PKR, FACT | [30] | |||
W | V | D | S149 | T | P | P | CSN | [22,23] | |
V | D | S | T150 | P | P | P | CSN | [22,23] | |
P | P | G | T155 | R | V | R | CSN | [22,23] | |
E | R | C | S183 | D | S | D | Aurora B | R/K-X-S/T (Aurara B) | [68] |
D | R | N | T211 | F | R | H | Aurora B | R/K-X-S/T (Aurara B) | [68] |
F | R | H | S215 | V | V | V | STK15, Aurora B | R/K-X-S/T (Aurara B) | [32] |
G | R | N | S269 | F | E | V | Aurora B | R/K-X-S/T (Aurara B) | [68] |
2.1.2. Acidic Residues Occur at Positions P−1 and P+1 Adjacent to Phosphorylation Sites in p53
Amino Acid Pair | P−1-P(S/T)-P+1 | P−2-P(S/T)-P+2 | P−3-P(S/T)-P+3 |
---|---|---|---|
D/S | 6 | 2 | 2 |
P/S | 6 | 6 | 8 |
S/Q | 5 | 2 | 2 |
S/T | 4 | 4 | 3 |
L/S | 3 | 3 | 2 |
E/T | 3 | 0 | 0 |
P/T | 3 | 2 | 4 |
S/S | 3 | 3 | 2 |
F/T | 3 | 1 | 0 |
V/S | 2 | 4 | 2 |
F/S | 2 | 0 | 2 |
R/S | 2 | 3 | 2 |
S/H | 2 | 2 | 1 |
S/G | 2 | 3 | 2 |
K/T | 1 | 0 | 0 |
T/G | 1 | 0 | 0 |
R/T | 1 | 3 | 1 |
S/N | 1 | 1 | 3 |
N/T | 1 | 0 | 0 |
S/Y | 1 | 0 | 1 |
S/C | 1 | 0 | 0 |
E/S | 0 | 3 | 3 |
Q/T | 0 | 2 | 1 |
A/S | 0 | 3 | 0 |
M/S | 0 | 1 | 1 |
W/T | 0 | 1 | 0 |
D/T | 0 | 2 | 2 |
A/T | 0 | 2 | 2 |
T/G | 0 | 1 | 1 |
V/T | 0 | 1 | 1 |
W/S | 0 | 0 | 2 |
K/S | 0 | 0 | 2 |
T/H | 0 | 0 | 2 |
M/T | 0 | 0 | 1 |
S/K | 0 | 1 | 0 |
2.1.3. Proline Residue in P−2, P−3, P+2, and P+3 Positions in the Phosphorylation Motifs
2.2. Cancer Mutations in p53 Phosphorylation Motif
2.2.1. D/S (E/T) Pairs Decrease while P/S Pair Increase Mutation Counts in p53 Phosphorylation Motif
pS/pT | P−3 | P−2 | P−1 | P0 | P +1 | P +2 | P +3 | Total | Amino Acid Pair |
---|---|---|---|---|---|---|---|---|---|
N- and C-Terminus Domains | |||||||||
S6 | 0 | 3 | 1 | 2 | 1 | 2 | 0 | 9 | D/S, Q/S |
S9 | 2 | 1 | 2 | 0 | 1 | 11 | 2 | 19 | P/S, V/S |
S15 | 2 | 1 | 0 | 1 | 1 | 1 | 0 | 6 | L/S, Q/S |
T18 | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 3 | E/T, F/T |
S20 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | D/S, F/S |
S33 | 1 | 2 | 0 | 1 | 1 | 3 | 1 | 9 | P/S, L/S |
S37 | 1 | 3 | 1 | 2 | 0 | 2 | 0 | 9 | P/S, Q/S |
S46 | 1 | 4 | 1 | 5 | 8 | 1 | 8 | 28 | P/S, L/S |
T55 | 1 | 4 | 2 | 0 | 5 | 0 | 2 | 14 | E/T, F/T |
T81 | 3 | 4 | 2 | 2 | 9 | 3 | 10 | 33 | P/T, P/T |
S99 | 6 | 3 | 6 | 4 | 1 | 4 | 7 | 31 | P/S, Q/S |
S106 | 0 | 3 | 11 | 8 | 5 | 3 | 6 | 36 | S/G, S/Y |
S313 | 4 | 6 | 8 | 4 | 1 | 3 | 2 | 28 | T/S, S/S |
S314 | 6 | 8 | 4 | 1 | 3 | 2 | 9 | 33 | S/S, S/S |
S315 | 8 | 4 | 1 | 3 | 2 | 9 | 3 | 30 | P/S, S/S |
S362 | 0 | 1 | 0 | 0 | 1 | 3 | 2 | 7 | S/G, R/S |
S366 | 2 | 3 | 2 | 2 | 0 | 0 | 0 | 9 | S/S, H/S |
S376 | 0 | 0 | 0 | 2 | 0 | 0 | 2 | 4 | Q/S, T/S |
T377 | 0 | 0 | 2 | 0 | 0 | 2 | 0 | 4 | S/S, S/S |
S378 | 0 | 2 | 0 | 0 | 2 | 0 | 0 | 4 | T/S, R/S |
T387 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 2 | E/T, T/K |
S392 | 1 | 0 | 0 | 1 | 0 | 2 | D/S, D/S | ||
Sum (N- and C-terminus) | 41 | 54 | 44 | 38 | 41 | 50 | 54 | ||
Core Domain | |||||||||
S149 | 14 | 32 | 16 | 16 | 14 | 190 | 141 | 423 | D/S, T/S |
T150 | 32 | 16 | 16 | 14 | 190 | 141 | 36 | 445 | T/S, P/T |
T155 | 141 | 36 | 85 | 79 | 85 | 228 | 247 | 901 | S/G, R/S |
S183 | 18 | 88 | 13 | 6 | 39 | 16 | 15 | 195 | S/D, S/C |
T211 | 39 | 15 | 14 | 30 | 16 | 81 | 87 | 282 | T/N, F/T |
S215 | 16 | 81 | 87 | 86 | 94 | 16 | 45 | 425 | S/H, S/V |
S269 | 187 | 57 | 17 | 20 | 102 | 54 | 169 | 606 | N/S, F/S |
Sum (core domain) | 447 | 325 | 248 | 251 | 540 | 726 | 740 |
2.2.2. Mutations Decrease the Propensity of Disorder in p53 Phosphorylation Motifs
3. Discussion
3.1. Why Is P/S (or P/T) Association More Vulnerable to Cancer Mutation?
3.2. Acidic Amino Acids Adjacent to Phosphorylation Sites in p53 Protein Families Can Provide Phosphorylation Redundancy
Peptides | Kd μm | Ref. | |||
---|---|---|---|---|---|
P300/TAZ1 | P300/TAZ2 | CBP/TAZ1 | CBP/TAZ2 | ||
P73(10–40) wt | 39 | 4.5 | [51] | ||
P73(10–40) pT14 | 4.6 | 0.47 | |||
P53(1–57) wt | 0.77 | [95] | |||
P53(1–57) pT18 | 0.11 | ||||
P53(10–57) wt | 0.88 | ||||
P53(10–57) pS15pS20 | 0.21 | ||||
P53(13–61) wt | 0.9 | 0.026 | [96] | ||
P53(13–57) pT18 | 0.5 | 0.05 | |||
P53(13–57) pS15pT18pT20 | 0.07 | 0.08 | |||
P53(1–39) wt | 0.43 (7.15) * | [97] * | |||
P53(1–39) pS15 | 0.05 (1.83) * | ||||
P53(1–39) pT18 | 0.05 (1.05) * | ||||
P53(1–39) pS15pT18 | 0.05 (1.74) * | ||||
Peptides | Kd μm | Ref. | |||
TFB1 | P62 (wt) | P62 (K18E) | |||
P53(25–65) wt | 0.39 | 3.18 | 3.63 | [98] | |
P53(25–65) pS46 | 0.15 | 0.52 | |||
P53(25–65) pT55 | 0.16 | 0.46 | |||
P53(25–65) pS46pT55 | 0.07 | 0.10 | 4.44 |
3.3. The Natively Disordered Nature of p53 Phosphorylation Motifs: Vulnerable or Resistant to Mutations?
3.4. Implications of Targeting p53 Mutants in Cancer Therapy
4. Materials and Methods
4.1. Amino Acid Pair Correlation and Propensities
4.2. Disorder Propensities of Phosphorylation Motif and Proteins in the p53/p63/p73 Family
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Ji, X.; Huang, Q.; Yu, L.; Nussinov, R.; Ma, B. Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs. Int. J. Mol. Sci. 2014, 15, 13275-13298. https://doi.org/10.3390/ijms150813275
Ji X, Huang Q, Yu L, Nussinov R, Ma B. Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs. International Journal of Molecular Sciences. 2014; 15(8):13275-13298. https://doi.org/10.3390/ijms150813275
Chicago/Turabian StyleJi, Xiaona, Qiang Huang, Long Yu, Ruth Nussinov, and Buyong Ma. 2014. "Bioinformatics Study of Cancer-Related Mutations within p53 Phosphorylation Site Motifs" International Journal of Molecular Sciences 15, no. 8: 13275-13298. https://doi.org/10.3390/ijms150813275