The structure of importin α and the nuclear localization peptide of ChREBP, and small compound inhibitors of ChREBP-importin a interactions

Hunmin Jung, Tomomi Takeshima, Tsutomu Nakagawa, Karen S. MacMillan, R. Max Wynn, Hanzhi Wang, Haruhiko Sakiyama, Shuguang Wei, Yang Li, Richard K. Bruick, Bruce A. Posner, Jef K. De Brabander, Kosaku Uyeda

Research output: Contribution to journalArticle

Abstract

The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in glucose-mediated induction of genes involved in hepatic glycolysis and lipogenesis. In response to fluctuating blood glucose levels ChREBP activity is regulated mainly by nucleocytoplasmic shuttling of ChREBP. Under high glucose ChREBP binds to importin α and importin β and translocates into the nucleus to initiate transcription. We have previously shown that the nuclear localization signal site (NLS) for ChREBP is bipartite with the NLS extending from Arg158 to Lys190. Here, we report the 2.5 Å crystal structure of the ChREBP-NLS peptide bound to importin a. The structure revealed that the NLS binding is monopartite, with the amino acid residues K171RRI174from the ChREBP-NLS interacting with ARM2-ARM5 on importin a. We discovered that importin α also binds to the primary binding site of the 14-3-3 proteins with high affinity, which suggests that both importin α and 14-3-3 are each competing with the other for this broad-binding region (residues 117-196) on ChREBP. We screened a small compound library and identified two novel compounds that inhibit the ChREBPNLS/ importin α interaction, nuclear localization, and transcription activities of ChREBP. These candidate molecules support developing inhibitors of ChREBP that may be useful in treatment of obesity and the associated diseases.

Original languageEnglish (US)
Pages (from-to)3253-3269
Number of pages17
JournalBiochemical Journal
Volume477
Issue number17
DOIs
StatePublished - Sep 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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