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- W2063402729 abstract "The production of insulin and islet amyloid polypeptide (IAPP) is limited to β-cells due to restricted expression of a set of tissue-specific transcription factors, the most well known of which is Pdx1. Naturally, insulin is expressed in much higher levels than IAPP, perhaps owing to the affinity of Pdx1 to its target sites. Like many transcription factors, Pdx1 contains regions of disorder whose function in transcription has not been adequately studied. It is well documented that the Pdx1 homeodomain binds to a core DNA recognition sequence containing the tetranucleotide TAAT, for which its consensus binding site is reported as 5′-CTCTAAT(T/G)AG-3′. Interestingly, while Pdx1 regulatory elements in the human insulin promoter conform to the pentanucleotide 5′-CTAAT-3′ sequence, the Pdx1 regulatory elements in the human iapp promoter contain a substitution to 5′-TTAAT-3′. The available crystal structure of Pdx1 bound to the consensus nucleotide sequence does not explain how the homeodomain would be able to identify the natural variation, if it does at all. Moreover, the structure of the c-terminal tail remains unknown, as is its contribution to the mechanism of target site selection. Here we report a combination of isothermal calorimetric titrations, NMR spectroscopy, and multi-microsecond molecular dynamics calculations of Pdx1 that define its interactions with a panel of natural promoter and consensus-derived sequences. Our results show a small preference of the Pdx1 homeodomain for 5′-CTAAT-3′. Molecular mechanics calculations, corroborated by experimental NMR data, lead to a rational explanation for sequence discrimination at this position. Regarding the 3′-position of the TAAT sequence, the addition of the dynamic c-terminal tail to the homeodomain provides additional sequence bias. Taken together, our results suggest a molecular mechanism for differential Pdx1 affinity to elements from the insulin and iapp promoter sequences." @default.
- W2063402729 created "2016-06-24" @default.
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- W2063402729 date "2014-01-01" @default.
- W2063402729 modified "2023-09-27" @default.
- W2063402729 title "Thermodynamic and Structural Studies of Pdx1 Binding to Elements from Natural Promoters and Near-Consensus Sites" @default.
- W2063402729 doi "https://doi.org/10.1016/j.bpj.2013.11.3854" @default.
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