title: Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity.
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.
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Helander
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Meri
authors.initials: M
authors.lastname: Montecchio
authors.affiliation: Division of Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Pilstål
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 92739, USA.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Clinical and Experimental Medicine, Cell Biology, Faculty of Health Science Linköping University, 58183 Linköping, Sweden.
authors.forename: Jacob
authors.initials: J
authors.lastname: Kuruvilla
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Elvén
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Javed M E
authors.initials: JME
authors.lastname: Ziauddin
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Madhanagopal
authors.initials: M
authors.lastname: Anandapadamanaban
authors.affiliation: Department of Clinical and Experimental Medicine, Cell Biology, Faculty of Health Science Linköping University, 58183 Linköping, Sweden.
authors.forename: Susana
authors.initials: S
authors.lastname: Cristobal
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Lundström
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 92739, USA.
authors.forename: Rosalie C
authors.initials: RC
authors.lastname: Sears
authors.affiliation: Division of Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Wallner
authors.affiliation: Division of Chemistry, Department of Physics, Chemistry and Biology, Linköping University, 58183 Linköping, Sweden. Electronic address: maria.sunnerhagen@liu.se.
authors.forename: Maria
authors.initials: M
authors.lastname: Sunnerhagen
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016271:Proto-Oncogene Proteins c-myc; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase