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

Sara Helander, Meri Montecchio, Robert Pilstål, Yulong Su, Jacob Kuruvilla, Malin Elvén, Javed M E Ziauddin, Madhanagopal Anandapadamanaban, Susana Cristobal, Patrik Lundström, Rosalie Sears, Björn Wallner, Maria Sunnerhagen

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20 Scopus citations

Abstract

Summary 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-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.

Original languageEnglish (US)
Pages (from-to)2267-2279
Number of pages13
JournalStructure
Volume23
Issue number12
DOIs
StatePublished - Dec 1 2015

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ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Helander, S., Montecchio, M., Pilstål, R., Su, Y., Kuruvilla, J., Elvén, M., Ziauddin, J. M. E., Anandapadamanaban, M., Cristobal, S., Lundström, P., Sears, R., Wallner, B., & Sunnerhagen, M. (2015). Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity. Structure, 23(12), 2267-2279. https://doi.org/10.1016/j.str.2015.10.010