Crystal structures reveal a new and novel FoxO1 binding site within the human glucose-6-phosphatase catalytic subunit 1 gene promoter

Singh, Puja; Han, Eun Hee; Endrizzi, James A.; O’Brien, Richard M.; Chi, Young‐In

doi:10.1016/j.jsb.2017.02.006

Cited by 20 publications

(21 citation statements)

References 63 publications

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“…Interestingly, the DIV motif was also detected, but not validated, using methyl-SELEX with full length FOXA1 ( 33 ) and high-throughput SELEX ( 32 ) for members of the FOXC subfamily. Further, we noticed that in a recently reported crystal structure of DNA bound FOXO1 an arrangement of crystallographically stacked DNA helices resembling the DIV configuration ( Supplementary Figure S7 ) ( 75 ). However, the authors did not test cooperative dimer formation on such an element.…”

Section: Discussionmentioning

confidence: 66%

DNA-mediated dimerization on a compact sequence signature controls enhancer engagement and regulation by FOXA1

Wang

Srivastava

Jankowski

et al. 2018

Nucleic Acids Research

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FOXA1 is a transcription factor capable to bind silenced chromatin to direct context-dependent cell fate conversion. Here, we demonstrate that a compact palindromic DNA element (termed ‘DIV’ for its diverging half-sites) induces the homodimerization of FOXA1 with strongly positive cooperativity. Alternative structural models are consistent with either an indirect DNA-mediated cooperativity or a direct protein-protein interaction. The cooperative homodimer formation is strictly constrained by precise half-site spacing. Re-analysis of chromatin immunoprecipitation sequencing data indicates that the DIV is effectively targeted by FOXA1 in the context of chromatin. Reporter assays show that FOXA1-dependent transcriptional activity declines when homodimeric binding is disrupted. In response to phosphatidylinositol-3 kinase inhibition DIV sites pre-bound by FOXA1 such as at the PVT1/MYC locus exhibit a strong increase in accessibility suggesting a role of the DIV configuration in the chromatin closed-open dynamics. Moreover, several disease-associated single nucleotide polymorphisms map to DIV elements and show allelic differences in FOXA1 homodimerization, reporter gene expression and are annotated as quantitative trait loci. This includes the rs541455835 variant at the MAPT locus encoding the Tau protein associated with Parkinson's disease. Collectively, the DIV guides chromatin engagement and regulation by FOXA1 and its perturbation could be linked to disease etiologies.

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Section: Discussionmentioning

confidence: 66%

DNA-mediated dimerization on a compact sequence signature controls enhancer engagement and regulation by FOXA1

Wang

Srivastava

Jankowski

et al. 2018

Nucleic Acids Research

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“…1A). Of note, crystal structures have been solved for the FOXO1 FHD (25,26), confirming a structured organization of this region. Next, we focused on the NTD and purified two recombinant proteins for structural examination using 2D NMR.…”

Section: The N-terminal Domain Of Foxo1 Is Intrinsically Disorderedmentioning

confidence: 68%

AMPK and AKT protein kinases hierarchically phosphorylate the N-terminus of the FOXO1 transcription factor, modulating interactions with 14-3-3 proteins

Saline

Badertscher

Wolter

et al. 2019

Journal of Biological Chemistry

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Edited by Wolfgang Peti Forkhead box protein O1 (FOXO1) is a transcription factor involved in various cellular processes such as glucose metabolism, development, stress resistance, and tumor suppression. FOXO1's transcriptional activity is controlled by different environmental cues through a myriad of posttranslational modifications. In response to growth factors, the serine/threonine kinase AKT phosphorylates Thr 24 and Ser 256 in FOXO1 to stimulate binding of 14-3-3 proteins, causing FOXO1 inactivation. In contrast, low nutrient and energy levels induce FOXO1 activity. AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, partly mediates this effect through phosphorylation of Ser 383 and Thr 649 in FOXO1. In this study, we identified Ser 22 as an additional AMPK phosphorylation site in FOXO1's N terminus, with Ser 22 phosphorylation preventing binding of 14-3-3 proteins. The crystal structure of a FOXO1 peptide in complex with 14-3-3 at 2.3 Å resolution revealed that this is a consequence of both steric hindrance and electrostatic repulsion. Furthermore, we found that AMPK-mediated Ser 22 phosphorylation impairs Thr 24 phosphorylation by AKT in a hierarchical manner. Thus, numerous mechanisms maintain FOXO1 activity via AMPK signaling. AMPK-mediated Ser 22 phosphorylation directly and indirectly averts binding of 14-3-3 proteins, whereas phosphorylation of Ser 383 and Thr 649 complementarily stimulates FOXO1 activity. Our results shed light on a mechanism that integrates inputs from both AMPK and AKT signaling pathways in a small motif to fine-tune FOXO1 transcriptional activity.

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“…FOXN2, FOXN3 and FOXM1 possess bi-specificity: They recognize both the FOX core sequence and the (GACGC) sequence for FOXN3 and FOXN4 and an inverted repeat for FOXM1 [106]. A non-canonical functional binding site has also been reported for FOXO1 [110].…”

Section: Non-canonical Bindingmentioning

confidence: 99%

The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

Schmitt-Ney

2020

Cells

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The nematode Caenorhabditis elegans possesses a unique (with various isoforms) FOXO transcription factor DAF-16, which is notorious for its role in aging and its regulation by the insulin-PI3K-AKT pathway. In humans, five genes (including a protein-coding pseudogene) encode for FOXO transcription factors that are targeted by the PI3K-AKT axis, such as in C. elegans. This common regulation and highly conserved DNA-binding domain are the pillars of this family. In this review, I will discuss the possible meaning of possessing a group of very similar proteins and how it can generate additional functionality to more complex organisms. I frame this discussion in relation to the much larger super family of Forkhead proteins to which they belong. FOXO members are very often co-expressed in the same cell type. The overlap of function and expression creates a certain redundancy that might be a safeguard against the accidental loss of FOXO function, which could otherwise lead to disease, particularly, cancer. This is one of the points that will be examined in this “family affair” report.

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Crystal structures reveal a new and novel FoxO1 binding site within the human glucose-6-phosphatase catalytic subunit 1 gene promoter

Cited by 20 publications

References 63 publications

DNA-mediated dimerization on a compact sequence signature controls enhancer engagement and regulation by FOXA1

DNA-mediated dimerization on a compact sequence signature controls enhancer engagement and regulation by FOXA1

AMPK and AKT protein kinases hierarchically phosphorylate the N-terminus of the FOXO1 transcription factor, modulating interactions with 14-3-3 proteins

The FOXO’s Advantages of Being a Family: Considerations on Function and Evolution

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