| Autor: |
Sarah A. Mosure, Paola Munoz-Tello, Kuang-Ting Kuo, Brian MacTavish, Xiaoyu Yu, Daniel Scholl, Christopher C. Williams, Timothy S. Strutzenberg, Jared Bass, Richard Brust, Ashok A. Deniz, Patrick R. Griffin, Douglas J. Kojetin |
| Rok vydání: |
2022 |
| Popis: |
PPARγ is a nuclear receptor transcription factor that regulates adipogenic and insulin sensitizing gene programs via two activation function (AF) regulatory domains: a ligand-dependent AF-2 coregulator interaction surface within the C-terminal ligand-binding domain (LBD) and an N-terminal disordered AF-1 domain (NTD or A/B region). Here, we show the AF-1 contains an evolutionary conserved Trp-Pro motif that populates two long-lived AF-1 conformations via proline cis/trans isomerization. The Trp-Pro motif participates in transient intradomain AF-1 contacts and interdomain contacts with two surfaces of the LBD (β-sheet and AF-2). Mutagenesis indicates the Pro residue negatively regulates PPARγ transcriptional output, suggesting a potential regulatory mechanism for AF-1 isomerization. Our findings provide a structural rationale to explain previous in vitro and cellular studies that reported interdomain functional communication between the PPARγ AF-1 and LBD. Our study also illuminates a structural biology platform to study how disordered domains in nuclear receptors influence their structure and function. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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