Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition
Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition
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DOI：
10.1073/pnas.1401180111
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发表时间：
2014-06-03
影响因子：
11.1
通讯作者：
Eigenbrot, Charles
中科院分区：
文献类型：
--
作者：
Lupardus, Patrick J.;Ultsch, Mark;Eigenbrot, Charles
Janus激酶（JAKs）是受体相关的多结构域酪氨酸激酶，作用于许多细胞因子和干扰素的下游。JAK激酶的活性受邻近的假激酶结构域的调控，其机制尚不清楚。在这里，我们报道了来自JAK家族成员TYK2的2.8埃双结构域假激酶-激酶模块的自抑制形式。我们发现假激酶和激酶在激酶活性位点附近相互作用，并且大多数报道的癌症相关的JAK等位基因突变聚集在这个界面或附近。TYK2界面附近残基的突变类似于癌症相关的JAK等位基因，包括V617F和“外显子12”JAK2突变，导致体外激酶活性增加。这些数据表明，JAK假激酶是一种自抑制结构域，它使激酶结构域保持不活性，直到受体二聚化刺激过渡到活性状态。
Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-angstrom structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state.