Crystal structures reveal a new and novel FoxO1 binding site within the human glucose-6-phosphatase catalytic subunit 1 gene promoter.
Crystal structures reveal a new and novel FoxO1 binding site within the human glucose-6-phosphatase catalytic subunit 1 gene promoter.
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DOI：
10.1016/j.jsb.2017.02.006
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发表时间：
2017-04
影响因子：
3
通讯作者：
Chi YI
中科院分区：
文献类型：
--
作者：
Singh P;Han EH;Endrizzi JA;O'Brien RM;Chi YI
人葡萄糖-6-磷酸酶在血糖稳态中起着至关重要的作用，有望成为糖尿病的治疗靶点。其催化亚单位基因1(G6PC1)的表达受代谢反应转录因子FoxO1和CREB的严格调控。尽管G6PC1启动子近端至少有三个潜在的FoxO1结合部位(胰岛素反应元件，IRES)和一个CREB结合部位(cAMP反应元件，CRE)已被确定，但FoxO1与CREB之间以及与多个IRES结合的FoxO1之间的相互作用尚未得到很好的描述。在这里，我们介绍了与G6PC1启动子形成的复合体中FoxO1DNA结合域的晶体结构。这些复合体揭示了与Cre重叠的新的非共识FoxO1结合位点的存在，暗示了G6PC1启动子上FoxO1和CREB结合的互斥机制。其他发现包括(I)非正则FoxO1识别位点，(Ii)可用IRE位点上的不完全FoxO1占有率，以及(Iii)可能在稳定DNA环中发挥作用的FoxO1二聚体相互作用。这些发现为了解FoxO1对G6PC1基因转录的调控提供了洞察力，并证明了FoxO1识别靶基因的高度多功能性，这与其在生物学中的不同角色有关。
Human glucose-6-phosphatase plays a vital role in blood glucose homeostasis and holds promise as a therapeutic target for diabetes. Expression of its catalytic subunit gene 1 (G6PC1) is tightly regulated by metabolic-response transcription factors such as FoxO1 and CREB. Although at least three potential FoxO1 binding sites (insulin response elements, IREs) and one CREB binding site (cAMP response element, CRE) within the proximal region of the G6PC1 promoter have been identified, the interplay between FoxO1 and CREB and between FoxO1 bound at multiple IREs has not been well characterized. Here we present the crystal structures of the FoxO1 DNA binding domain in complex with the G6PC1 promoter. These complexes reveal the presence of a new non-consensus FoxO1 binding site that overlaps the CRE, suggesting a mutual exclusion mechanism for FoxO1 and CREB binding at the G6PC1 promoter. Additional findings include (i) non-canonical FoxO1 recognition sites, (ii) incomplete FoxO1 occupancies at the available IRE sites, and (iii) FoxO1 dimeric interactions that may play a role in stabilizing DNA looping. These findings provide insight into the regulation of G6PC1 gene transcription by FoxO1, and demonstrate a high versatility of target gene recognition by FoxO1 that correlates with its diverse roles in biology.