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Structural characterization of human tryptophan hydroxylase 2 reveals that L-Phe is superior to L-Trp as the regulatory domain ligand
Structure ( IF 5.7 ) Pub Date : 2023-04-28 , DOI: 10.1016/j.str.2023.04.004
Ida M Vedel 1 , Andreas Prestel 2 , Zhenwei Zhang 3 , Natalia T Skawinska 1 , Holger Stark 3 , Pernille Harris 4 , Birthe B Kragelund 2 , Günther H J Peters 1
Affiliation  

Tryptophan hydroxylase 2 (TPH2) catalyzes the rate-limiting step in serotonin biosynthesis in the brain. Consequently, regulation of TPH2 is relevant for serotonin-related diseases, yet the regulatory mechanism of TPH2 is poorly understood and structural and dynamical insights are missing. We use NMR spectroscopy to determine the structure of a 47 N-terminally truncated variant of the regulatory domain (RD) dimer of human TPH2 in complex with L-Phe, and show that L-Phe is the superior RD ligand compared with the natural substrate, L-Trp. Using cryo-EM, we obtain a low-resolution structure of a similarly truncated variant of the complete tetrameric enzyme with dimerized RDs. The cryo-EM two-dimensional (2D) class averages additionally indicate that the RDs are dynamic in the tetramer and likely exist in a monomer-dimer equilibrium. Our results provide structural information on the RD as an isolated domain and in the TPH2 tetramer, which will facilitate future elucidation of TPH2’s regulatory mechanism.



中文翻译:

人色氨酸羟化酶 2 的结构表征表明,L-Phe 作为调节域配体优于 L-Trp

色氨酸羟化酶 2 (TPH2) 催化大脑中血清素生物合成的限速步骤。因此,TPH2 的调节与血清素相关疾病相关,但人们对 TPH2 的调节机制知之甚少,并且缺乏结构和动力学见解。我们使用核磁共振光谱确定与 L-Phe 复合的人 TPH2 调节域 (RD) 二聚体的 47 N 末端截短变体的结构,并表明与天然底物 L-Trp 相比,L-Phe 是更好的 RD 配体. 使用低温 EM,我们获得了具有二聚化 RD 的完整四聚体酶的类似截短变体的低分辨率结构。cryo-EM 二维 (2D) 类平均值还表明 RD 在四聚体中是动态的,并且可能存在于单体-二聚体平衡中。我们的结果提供了关于作为独立域的 RD 和 TPH2 四聚体的结构信息,这将有助于未来阐明 TPH2 的调控机制。

更新日期:2023-04-28
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