Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
2015 (English)In: Structure, ISSN 0969-2126, E-ISSN 1878-4186, Vol. 23, no 12, 2267-2279 p.Article in journal (Refereed) Published
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
Place, publisher, year, edition, pages
Cell Press , 2015. Vol. 23, no 12, 2267-2279 p.
IdentifiersURN: urn:nbn:se:liu:diva-106184DOI: 10.1016/j.str.2015.10.010OAI: oai:DiVA.org:liu-106184DiVA: diva2:714463
The previous status of this article was Manuscript and the original title was Pre-anchoring of Pin1 to unphosphorylated c-Myc in a dynamic complex affects c-Myc stability andactivity.
Funding Agencies|Knut and Alice Wallenberg Foundation; Swedish Cancer Foundation; Swedish Child Cancer Foundation; Carl Trygger foundation; LiU Cancer Research Network; Swedish Research Council; NCI [R01s CA129040, CA100855]2014-04-282014-04-282016-04-29Bibliographically approved