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The N-Terminal Integrity Is Critical for the Stability and Biological Functionsof Endostatint

机译：N端完整性对于内皮抑素的稳定性和生物学功能至关重要

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Endostatin is an endogenous angiogenesis inhibitor, and amino acid residues HI, H3, Hit, and D76 at its N-terminus coordinate with one zinc ion. Recombinant endostatin suffering from N-terminal truncations during Pichia pastoris expression was widely used in previous studies and generated inconsistent antitumor results. However, little attention was paid to the possible alteration on the stability and activity of endostatin caused by N-terminal truncations. In this study, N-terminally truncated forms of endostatin expressed by P. pastoris are identified as N-1, N-3, and N-4, in which one or two of the four zinc-binding residues are lost. The N-terminal truncation of the first amino acid residue (H) does not result in a significant change in the conformation, zinc-binding capacity, thermodynamic stability, or biological activity, while truncations of the first three amino acid residues (FISH) or the first four amino acid residues (HSHR) dramatically decrease the thermodynamic stability measured by urea-induced unfolding and biological activities of endostatin both in vitro and in vivo. Intriguingly, ZBP-endostatin with a short extra zinc-binding peptide (ZBP) engineered at the N-terminus exhibits a more tightly packed tertiary structure and increased thermodynamic stability and cooperativity against urea, with more potent antiendothelial and antitumor activities than the wild-type endostatin. These findings demonstrate that the N-terminal integrity is essential for the stability and biological functions of endostatin, which provides fundamental explanations for the inconsistent antitumor activities of endostatin in a variety of studies, including the different therapeutic efficacies of endostatin and ZBP-endostatin in clinical trials
机译：内皮抑素是一种内源性血管生成抑制剂，其N端的氨基酸残基HI，H3，Hit和D76与一个锌离子配位。在巴斯德毕赤酵母表达过程中遭受N端截短的重组内皮抑素在先前的研究中被广泛使用，并产生不一致的抗肿瘤​​结果。然而，很少有人关注由N末端截短引起的内皮抑素的稳定性和活性改变。在这项研究中，巴斯德毕赤酵母表达的内皮抑素的N端截短形式被鉴定为N-1，N-3和N-4，其中四个锌结合残基中的一个或两个丢失。第一个氨基酸残基（H）的N末端截短不会导致构象，锌结合能力，热力学稳定性或生物学活性发生显着变化，而前三个氨基酸残基（FISH）或前四个氨基酸残基（HSHR）大大降低了尿素诱导的内皮抑素的体外和体内生物活性和生物活性测得的热力学稳定性。有趣的是，在N端经过工程改造的ZBP-内皮抑素和一个短的额外锌结合肽（ZBP）表现出更紧密的三级结构，增加了对尿素的热力学稳定性和协同性，比野生型具有更强的抗内皮和抗肿瘤活性内皮抑素。这些发现表明，N-末端完整性对于内皮抑素的稳定性和生物学功能至关重要，这为内皮抑素在多种研究中抗肿瘤活性不一致的现象提供了基本解释，包括内皮抑素和ZBP-内皮抑素在临床上的不同治疗功效。试验

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