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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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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Phosphorylation
Surface Plasmon Resonance
Oncogene Proteins
Catalysis
Proline
Half-Life
Catalytic Domain
Magnetic Resonance Spectroscopy
Cell Proliferation
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Helander, S., Montecchio, M., Pilstål, R., Su, Y., Kuruvilla, J., Elvén, M., ... 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

Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity. / Helander, Sara; Montecchio, Meri; Pilstål, Robert; Su, Yulong; Kuruvilla, Jacob; Elvén, Malin; Ziauddin, Javed M E; Anandapadamanaban, Madhanagopal; Cristobal, Susana; Lundström, Patrik; Sears, Rosalie; Wallner, Björn; Sunnerhagen, Maria.

In: Structure, Vol. 23, No. 12, 01.12.2015, p. 2267-2279.

Research output: Contribution to journalArticle

Helander, S, Montecchio, M, Pilstål, R, Su, Y, Kuruvilla, J, Elvén, M, Ziauddin, JME, 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, vol. 23, no. 12, pp. 2267-2279. https://doi.org/10.1016/j.str.2015.10.010
Helander S, Montecchio M, Pilstål R, Su Y, Kuruvilla J, Elvén M et al. Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity. Structure. 2015 Dec 1;23(12):2267-2279. https://doi.org/10.1016/j.str.2015.10.010
Helander, Sara ; Montecchio, Meri ; Pilstål, Robert ; Su, Yulong ; Kuruvilla, Jacob ; Elvén, Malin ; Ziauddin, Javed M E ; Anandapadamanaban, Madhanagopal ; Cristobal, Susana ; Lundström, Patrik ; Sears, Rosalie ; Wallner, Björn ; Sunnerhagen, Maria. / Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity. In: Structure. 2015 ; Vol. 23, No. 12. pp. 2267-2279.
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