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Human Nek6 is a monomeric mostly globular kinase with an unfolded short N-terminal domain

机译:人Nek6是具有未折叠的短N端结构域的单体主要是球状激酶

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摘要

Background: The NIMA-related kinases (Neks) are widespread among eukaryotes. In mammalians they represent an evolutionarily conserved family of 11 serine/threonine kinases, with 40 45% amino acid sequence identity to the Aspergillus nidulans mitotic regulator NIMA within their catalytic domains. Neks have cell cycle-related functions and were recently described as related to pathologies, particularly cancer, consisting in potential chemotherapeutic targets. Human Nek6, -7 and -9 are involved in the control of mitotic spindle formation, acting together in a mitotic kinase cascade, but their mechanism of regulation remain elusive. Results: In this study we performed a biophysical and structural characterization of human Nek6 with the aim of obtaining its low resolution and homology models. SAXS experiments showed that hNek6 is a monomer of a mostly globular, though slightly elongated shape. Comparative molecular modeling together with disorder prediction analysis also revealed a flexible disordered N-terminal domain for hNek6, which we found to be important to mediate interactions with diverse partners. SEC-MALS experiments showed that hNek6 conformation is dependent on its activation/phosphorylation status, a higher phosphorylation degree corresponding to a bigger Stokes radius. Circular dichroism spectroscopy confirmed our in silico predictions of secondary structure content and thermal stability shift assays revealed a slightly higher stability of wild-type hNek6 compared to the activation loop mutant hNek6(S206A). Conclusions: Our data present the first low resolution 3D structure of hNek6 protein in solution. SAXS, comparative modeling and SEC-MALS analysis revealed that hNek6 is a monomeric kinase of slightly elongated shape and a short unfolded N-terminal domain.
机译:背景:NIMA相关激酶(Neks)在真核生物中广泛分布。在哺乳动物中,它们代表11个丝氨酸/苏氨酸激酶的进化保守家族,在其催化域内与构巢曲霉有丝分裂调节剂NIMA具有40 45%的氨基酸序列同一性。痣具有与细胞周期有关的功能,最近被描述为与病理相关,特别是与癌症有关的疾病,其包括潜在的化学治疗靶标。人Nek6,-7和-9参与有丝分裂纺锤体形成的控制,在有丝分裂激酶级联反应中共同发挥作用,但其调控机制仍不清楚。结果:在这项研究中,我们进行了人类Nek6的生物物理和结构表征,旨在获得其低分辨率和同源性模型。 SAXS实验表明,hNek6是主要呈球形的单体,尽管形状稍长。比较分子建模以及疾病预测分析也揭示了hNek6的柔性无序N末端结构域,我们发现这对于介导与不同伴侣的相互作用很重要。 SEC-MALS实验表明,hNek6构象取决于其激活/磷酸化状态,磷酸化程度越高,斯托克斯半径越大。圆二色光谱法证实了我们对二级结构含量的计算机模拟,热稳定性变化分析表明,与激活环突变体hNek6(S206A)相比,野生型hNek6的稳定性稍高。结论:我们的数据显示了溶液中hNek6蛋白的第一个低分辨率3D结构。 SAXS,比较模型和SEC-MALS分析表明,hNek6是一种单体激酶,其形状略微细长,且具有一个短的未折叠N端结构域。

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