Nucleotide Binding, Evolutionary Insights, and Interaction Partners of the Pseudokinase Unc-51-like Kinase 4.
Nucleotide Binding, Evolutionary Insights, and Interaction Partners of the Pseudokinase Unc-51-like Kinase 4.
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假激酶 Unc-51 样激酶 4 的核苷酸结合、进化见解和相互作用伙伴。
DOI：
10.1016/j.str.2020.07.016
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Knapp,Stefan
中科院分区：
文献类型：
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作者：
Preuss,Franziska;Chatterjee,Deep;Mathea,Sebastian;Shrestha,Safal;St-Germain,Jonathan;Saha,Manipa;Kannan,Natarajan;Raught,Brian;Rottapel,Robert;Knapp,Stefan
Unc-51样激酶4（ULK 4）是一种假激酶，与多种疾病的发生有关。即使激酶中ATP结合所需的序列基序缺乏，ULK 4仍然紧密结合ATP，并且辅助因子的存在是ULK 4的结构稳定性所需的。在这里，我们展示了ULK 4-ATPγS复合物的高分辨率结构，揭示了一种非常不寻常的ATP结合模式，其中缺乏典型的VAIK基序赖氨酸被位于αC N端的K39补偿。进化分析表明，在后生动物ULK 4的活性位点基序的降解已共同发生的ULK 4特异性激活环，稳定的C螺旋。此外，使用BioID和生物化学验证数据的细胞相互作用研究揭示了假激酶和犰狳重复结构域的高置信度相互作用。许多已鉴定的ULK 4相互作用伴侣是中心体和微管蛋白相关蛋白以及几种活性激酶，这表明ULK 4具有有趣的调节作用。
Unc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the co-factor is required for structural stability of ULK4. Here, we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4-specific activation loop, which stabilizes the C helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin-associated proteins and several active kinases suggesting interesting regulatory roles for ULK4.