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 language | English (US) |
|---|---|
| Pages (from-to) | 2267-2279 |
| Number of pages | 13 |
| Journal | Structure |
| Volume | 23 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 1 2015 |
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ASJC Scopus subject areas
- Molecular Biology
- Structural Biology
Cite this
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 journal › Article
}
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
AU - Wallner, Björn
AU - Sunnerhagen, Maria
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.
UR - http://www.scopus.com/inward/record.url?scp=84949322627&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84949322627&partnerID=8YFLogxK
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 -