Therapeutically, targeting the pro- and anti-apoptotic proteins has been one of the major approaches behind devising strategies to combat associated diseases. Human high-temperature requirement serine protease A2 (hHtrA2), which induces apoptosis through both caspase-dependent and independent pathways is implicated in several diseases including cancer, ischemic heart diseases, and neurodegeneration, thus making it a promising target molecule. In the recent past, the canine model has gained prominence in the understanding of human pathophysiology that was otherwise limited to the rodent system. Moreover, canine models in cancer research provide an opportunity to study spontaneous tumors as their size, lifespan, and environmental exposure are significantly closer to that of humans compared with laboratory rodents. Therefore, using HtrA2 as a model protein, comparative analysis has been done to revisit the hypothesis that canines might be excellent models for cancer research. We have performed evolutionary phylogenetic analyses that confirm a close relationship between canine and human HtrA2s. Molecular modeling demonstrates structural similarities including orientation of the catalytic triad residues, followed by in silico docking and molecular dynamics simulation studies that identify the potential interacting partners for canine HtrA2 (cHtrA2). In vitro biophysical and protease studies depict similarities in interaction with their respective substrates as well as transient transfection of cHtrA2 in mammalian cell culture shows induction of apoptosis. This work, therefore, promises to open a new avenue in cancer research through the study of spontaneous cancer model systems in canines.

中文翻译：

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犬和人 HtrA2 的比较分析，以描述其在细胞凋亡和癌症中的作用。


在治疗方面，靶向促凋亡蛋白和抗凋亡蛋白一直是设计对抗相关疾病策略的主要方法之一。人高温需求丝氨酸蛋白酶 A2 （hHtrA2） 通过 caspase 依赖性和非依赖性途径诱导细胞凋亡，与癌症、缺血性心脏病和神经退行性变等多种疾病有关，因此使其成为一种有前途的靶分子。最近，犬类模型在理解人类病理生理学方面获得了突出地位，否则这些病理生理学仅限于啮齿动物系统。此外，癌症研究中的犬类模型为研究自发性肿瘤提供了机会，因为与实验室啮齿动物相比，它们的大小、寿命和环境暴露明显更接近人类。因此，使用 HtrA2 作为模型蛋白，已经进行了比较分析，以重新审视犬科动物可能是癌症研究的优秀模型的假设。我们进行了进化系统发育分析，证实了犬类和人类 HtrA2 之间的密切关系。分子建模显示了结构相似性，包括催化三联体残基的取向，然后是计算机对接和分子动力学模拟研究，以确定犬 HtrA2 （cHtrA2） 的潜在相互作用伙伴。体外生物物理和蛋白酶研究描述了与它们各自底物相互作用的相似性，并且在哺乳动物细胞培养物中瞬时转染 cHtrA2 显示诱导细胞凋亡。因此，这项工作有望通过研究犬科动物的自发性癌症模型系统，为癌症研究开辟一条新途径。