Highly Conserved C-Terminal Region of Indian Hedgehog N-Fragment Contributes to Its Auto-Processing and Multimer Formation.
Highly Conserved C-Terminal Region of Indian Hedgehog N-Fragment Contributes to Its Auto-Processing and Multimer Formation.
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DOI：
10.3390/biom11060792
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发表时间：
2021-05-25
期刊：
影响因子：
5.5
通讯作者：
Ma G
中科院分区：
文献类型：
--
作者：
Wang X;Liu H;Liu Y;Han G;Wang Y;Chen H;He L;Ma G
Hedgehog （HH）是一个高度保守的分泌性信号蛋白家族，主要参与胚胎发育、体内平衡和肿瘤发生。HH通常作为前体合成，随后进行自蛋白水解裂解，产生氨基末端片段（HH- n），介导信号传导，以及羧基末端片段（HH- c），催化自动加工反应。HH- n的n端区域是HH多聚体形成以促进信号转导所必需的，而HH- n的c端区域的功能尚不明确。本研究以HH家族成员印度刺猬（IHH）为研究对象，通过蛋白截断、细胞检测和三维结构预测等方法，探索IHH （IHH- n）氨基末端片段c端区域的功能。结果表明，通过插入IHH-N蛋白相互结合形成多聚体，S195、A196和A197三个氨基酸是至关重要的。K191、S192、E193和H194对IHH自裂的影响非常显著。此外，A198、K199和T200对IHH-N的稳定性有明显影响。本研究提示IHH- n的c端在IHH的生理功能中多个层面发挥重要作用，从而加深了对HH生化特性的认识。
Hedgehog (HH) is a highly conserved secretory signalling protein family mainly involved in embryonic development, homeostasis, and tumorigenesis. HH is generally synthesised as a precursor, which subsequently undergoes autoproteolytic cleavage to generate an amino-terminal fragment (HH-N), mediating signalling, and a carboxyl-terminal fragment (HH-C), catalysing the auto-processing reaction. The N-terminal region of HH-N is required for HH multimer formation to promote signal transduction, whilst the functions of the C-terminal region of HH-N remain ambiguous. This study focused on Indian Hedgehog (IHH), a member of the HH family, to explore the functions of the C-terminal region of the amino-terminal fragment of IHH (IHH-N) via protein truncation, cell-based assays, and 3D structure prediction. The results revealed that three amino acids, including S195, A196, and A197, were crucial for the multimer formation by inserting the mutual binding of IHH-N proteins. K191, S192, E193, and H194 had an extremely remarkable effect on IHH self-cleavage. In addition, A198, K199, and T200 evidently affected the stability of IHH-N. This work suggested that the C-terminus of IHH-N played an important role in the physiological function of IHH at multiple levels, thus deepening the understanding of HH biochemical properties.
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