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 C Sears, Björn Wallner, Maria Sunnerhagen

Journal: Structure (London, England : 1993) 2016;23(12):2267-2279

PMID: 26655473

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Abstract

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.

Address: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.; Division of Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 92739, USA.; Department of Clinical and Experimental Medicine, Cell Biology, Faculty of Health Science Linköping University, 58183 Linköping, Sweden.; Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden. Electronic address: [email protected].

DOI: 10.1016/j.str.2015.10.010

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MeSH Terms: Amino Acid Sequence, Binding Sites, Humans, Molecular Sequence Data, Mutation, NIMA-Interacting Peptidylprolyl Isomerase, Peptidylprolyl Isomerase, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-myc