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Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
被引:43
作者:

Helander, Sara
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Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Montecchio, Meri
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Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Pilstal, Robert
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Linkoping Univ, Dept Phys Chem & Biol, Div Bioinformat, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Su, Yulong
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Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Kuruvilla, Jacob
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机构:
Linkoping Univ, Fac Hlth Sci, Cell Biol, Dept Clin & Expt Med, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Elven, Malin
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Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Ziauddin, Javed M. E.
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Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Anandapadamanaban, Madhanagopal
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Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Cristobal, Susana
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Linkoping Univ, Fac Hlth Sci, Cell Biol, Dept Clin & Expt Med, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Lundstrom, Patrik
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Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Sears, Rosalie C.
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Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Wallner, Bjorn
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Linkoping Univ, Dept Phys Chem & Biol, Div Bioinformat, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden

Sunnerhagen, Maria
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h-index: 0
机构:
Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden
机构:
[1] Linkoping Univ, Dept Phys Chem & Biol, Div Chem, S-58183 Linkoping, Sweden
[2] Linkoping Univ, Dept Phys Chem & Biol, Div Bioinformat, S-58183 Linkoping, Sweden
[3] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA
[4] Linkoping Univ, Fac Hlth Sci, Cell Biol, Dept Clin & Expt Med, S-58183 Linkoping, Sweden
来源:
基金:
瑞典研究理事会;
关键词:
TRANSACTIVATION DOMAIN;
SUBSTRATE RECOGNITION;
STRUCTURAL BASIS;
R REGION;
PHOSPHORYLATION;
BINDING;
PHOSPHOSERINE;
ISOMERASE;
DEGRADATION;
PROTEOLYSIS;
D O I:
10.1016/j.str.2015.10.010
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:
Hierarchic phosphorylation and concomitant Pin1-mediated proline isomerization of the oncoprotein c-Myc controls its cellular stability and activity. However, the molecular basis for Pin1 recognition and catalysis of c-Myc and other multisite, disordered substrates in cell regulation and disease is unclear. By nuclear magnetic resonance, surface plasmon resonance, and molecular modeling, we show that Pin1 subdomains jointly pre-anchor unphosphorylated c-Myc(1-88) in the Pin1 interdomain cleft in a disordered, or "fuzzy'', complex at the herein named Myc Box 0 (MB0) conserved region N-terminal to the highly conserved Myc Box I (MBI). Ser62 phosphorylation in MBI intensifies previously transient MBI-Pin1 interactions in c-Myc(1-88) binding, and increasingly engages Pin1(PPIase) and its catalytic region with maintained MB0 interactions. In cellular assays, MB0 mutated c-Myc shows decreased Pin1 interaction, increased protein half-life, but lowered rates of Myc-driven transcription and cell proliferation. We propose that dynamic Pin1 recognition of MB0 contributes to the regulation of c-Myc activity in cells.
引用
收藏
页码:2267 / 2279
页数:13
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