TY - JOUR
T1 - Pre-Anchoring of Pin1 to Unphosphorylated c-Myc in a Fuzzy Complex Regulates c-Myc Activity
AU - Helander, Sara
AU - Montecchio, Meri
AU - Pilstål, Robert
AU - Su, Yulong
AU - Kuruvilla, Jacob
AU - Elvén, Malin
AU - Ziauddin, Javed M.E.
AU - Anandapadamanaban, Madhanagopal
AU - Cristobal, Susana
AU - Lundström, Patrik
AU - Sears, Rosalie C.
AU - Wallner, Björn
AU - Sunnerhagen, Maria
N1 - Funding Information:
We acknowledge Drs. Cecilia Andresen, Veronika Csizmok, Julie Forman-Kay, and Linda Penn for critical discussion, Dr. Peter Bayer for sharing human Pin1, Pin1 WW , and Pin1 PPIase expression constructs, Marie Roth for protein production, the Swedish NMR Center (SNC) and SWEDSTRUCT for access to NMR spectrometers, and the Knut and Alice Wallenberg Foundation for equipment grants to LiU and SNC. Project funding is acknowledged from the Swedish Cancer Foundation (M.S.), the Swedish Child Cancer Foundation (M.S.), the Carl Trygger foundation (M.S.), the LiU Cancer Research Network (M.S.), the Swedish Research Council (S.C., P.L., M.S., B.W.), and the NCI R01s CA129040 and CA100855 (R.S.).
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2015.10.010
DO - 10.1016/j.str.2015.10.010
M3 - Article
C2 - 26655473
AN - SCOPUS:84949322627
VL - 23
SP - 2267
EP - 2279
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 12
ER -