Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein
Mechanism of activation of NDR (nuclear Dbf2-related) protein kinase by the hMOB1 protein
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DOI：
10.1074/jbc.m404542200
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发表时间：
2004-08-20
影响因子：
4.8
通讯作者：
Hemmings, BA
中科院分区：
文献类型：
--
作者：
Bichsel, SJ;Tamaskovic, R;Hemmings, BA
NDR（核Dbf 2相关）激酶属于在整个真核世界中高度保守的激酶家族。我们以前表明，NDR是由磷酸化和钙离子结合蛋白，S100 B。人类NDR的芽殖酵母亲属Cbk 1和Dbf 2分别与Mob 2（Mps one binder 2）和Mob 1相互作用。这种相互作用是这些激酶的活性和生物学功能所必需的。在这项研究中，我们表明，hMOB 1，最接近的亲戚酵母Mob 1和Mob 2，刺激NDR激酶活性，并与NDR在体内和体外相互作用。NDR的N-末端结构域内的高度保守残基的点突变降低了NDR激酶活性以及人MOB 1结合。NDR激酶的一个新特征是在亚结构域VII和VIII之间的催化结构域内插入。该插入片段内的氨基酸序列显示在已知与MOB蛋白相互作用的NDR家族的所有激酶中具有高碱性氨基酸含量。我们表明，这个序列是自抑制的，我们的数据表明，人MOB 1的N-末端结构域的NDR的结合诱导释放这种自抑制。
NDR (nuclear Dbf2-related) kinase belongs to a family of kinases that is highly conserved throughout the eukaryotic world. We showed previously that NDR is regulated by phosphorylation and by the Ca2+-binding protein, S100B. The budding yeast relatives of Homo sapiens NDR, Cbk1, and Dbf2, were shown to interact with Mob2 (Mps one binder 2) and Mob1, respectively. This interaction is required for the activity and biological function of these kinases. In this study, we show that hMOB1, the closest relative of yeast Mob1 and Mob2, stimulates NDR kinase activity and interacts with NDR both in vivo and in vitro. The point mutations of highly conserved residues within the N-terminal domain of NDR reduced NDR kinase activity as well as human MOB1 binding. A novel feature of NDR kinases is an insert within the catalytic domain between subdomains VII and VIII. The amino acid sequence within this insert shows a high basic amino acid content in all of the kinases of the NDR family known to interact with MOB proteins. We show that this sequence is autoinhibitory, and our data indicate that the binding of human MOB1 to the N-terminal domain of NDR induces the release of this autoinhibition.