Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes.
Kinase domain autophosphorylation rewires the activity and substrate specificity of CK1 enzymes.
复制标题
DOI：
10.1016/j.molcel.2022.03.005
复制
发表时间：
2022-06-02
期刊：
影响因子：
16
通讯作者：
Gould, Kathleen L.
中科院分区：
文献类型：
--
作者：
Cullati, Sierra N.;Chaikuad, Apirat;Chen, Jun-Song;Gebel, Jakob;Tesmer, Laura;Zhubi, Rezart;Navarrete-Perea, Jose;Guillen, Rodrigo X.;Gygi, Steven P.;Hummer, Gerhard;Dotsch, Volker;Knapp, Stefan;Gould, Kathleen L.
CK1是一种嗜酸性丝氨酸/苏氨酸激酶，具有多种重要的细胞功能；它们的错误调节导致癌症、神经退行性疾病和睡眠时相障碍。在这里，我们描述了CK1活性的一种进化保守的机制：位于底物结合裂隙附近的螺旋δG的N端的苏氨酸(人CK1α中的T220)的自磷酸化。晶体结构和分子动力学模拟揭示了αG的固有可塑性，这种可塑性在T220自动磷酸化后增加。磷酸化诱导的结构变化显著改变底物结合裂解的构象，影响底物特异性。在T220磷酸化的酵母和人CK1中，对许多底物的活性降低，但我们也发现了一种高亲和力底物，该底物被更快地磷酸化，定量磷酸蛋白质组学表明，干扰T220自动磷酸化重新连接了裂殖酵母中的CK1信号。T220只存在于CK1家族，因此它的自动磷酸化可能已经进化为这个重要家族的一种独特的调节机制。Cullati等人的研究。发现CK1酶在其激活区中自动磷酸化保守的苏氨酸。该位点的磷酸化改变底物结合裂解的构象，影响底物的特异性。CK1在许多不同的信号通路中以底物为靶标，这一机制可能调节不同条件下哪些底物被磷酸化。
CK1s are acidophilic serine/threonine kinases with multiple critical cellular functions; their misregulation contributes to cancer, neurodegenerative diseases, and sleep phase disorders. Here, we describe an evolutionarily conserved mechanism of CK1 activity: autophosphorylation of a threonine (T220 in human CK1δ) located at the N-terminus of helix αG, proximal to the substrate binding cleft. Crystal structures and molecular dynamics simulations uncovered inherent plasticity in αG that increased upon T220 autophosphorylation. The phosphorylation-induced structural changes significantly altered the conformation of the substrate binding cleft, affecting substrate specificity. In T220 phosphorylated yeast and human CK1s, activity toward many substrates was decreased, but we also identified a high-affinity substrate that was phosphorylated more rapidly, and quantitative phosphoproteomics revealed that disrupting T220 autophosphorylation rewired CK1 signaling in Schizosaccharomyces pombe. T220 is present exclusively in the CK1 family, thus its autophosphorylation may have evolved as a unique regulatory mechanism for this important family. Cullati et al. discovered that CK1 enzymes autophosphorylate a conserved threonine in their kinase domains. Phosphorylation at this site alters the conformation of the substrate binding cleft, affecting substrate specificity. CK1 targets substrates in many different signaling pathways, and this mechanism may regulate which are phosphorylated under different conditions.
登录
查看更多内容
影响因子：
4.8
作者：
Bernatik, Ondrej;Ganji, Ranjani Sri;Bryja, Vitezslav
通讯作者：
Bryja, Vitezslav
影响因子：
4
作者：
Casagolda, David;del Valle-Perez, Beatriz;Dunach, Mireia
通讯作者：
Dunach, Mireia
影响因子：
3.7
作者：
Eng, Gracie Wee Ling;Edison;Virshup, David M.
通讯作者：
Virshup, David M.
影响因子：
3.3
作者：
Elmore, Zachary C.;Guillen, Rodrigo X.;Gould, Kathleen L.
通讯作者：
Gould, Kathleen L.
影响因子：
64.8
作者：
Bishop, AC;Ubersax, JA;Shokat, KM
通讯作者：
Shokat, KM