1. Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
- Author
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Björn Wallner, Yulong Su, Malin Elvén, Jacob Kuruvilla, Maria Sunnerhagen, Sara Helander, Susana Cristobal, Patrik Lundström, Madhanagopal Anandapadamanaban, Javed M.E. Ziauddin, Robert Pilstål, Meri Montecchio, and Rosalie C. Sears
- Subjects
Peptidylprolyl isomerase ,Binding Sites ,Cell growth ,Molecular Sequence Data ,Plasma protein binding ,Peptidylprolyl Isomerase ,Biology ,Article ,Cell biology ,NIMA-Interacting Peptidylprolyl Isomerase ,Proto-Oncogene Proteins c-myc ,Biochemistry ,Transcription (biology) ,Structural Biology ,Mutation ,PIN1 ,Humans ,Phosphorylation ,Amino Acid Sequence ,Binding site ,Protein Processing, Post-Translational ,Molecular Biology ,Protein Binding - Abstract
SummaryHierarchic 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-Myc1–88 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-Myc1–88 binding, and increasingly engages Pin1PPIase 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.
- Published
- 2015
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