Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity

被引:43
作者
Helander, Sara [1 ]
Montecchio, Meri [1 ]
Pilstal, Robert [2 ]
Su, Yulong [3 ]
Kuruvilla, Jacob [4 ]
Elven, Malin [1 ]
Ziauddin, Javed M. E. [1 ]
Anandapadamanaban, Madhanagopal [1 ]
Cristobal, Susana [4 ]
Lundstrom, Patrik [1 ]
Sears, Rosalie C. [3 ]
Wallner, Bjorn [2 ]
Sunnerhagen, Maria [1 ]
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
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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