Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme
Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme
复制标题
DOI：
10.1016/j.cell.2005.10.029
复制
发表时间：
2005-12-02
期刊：
影响因子：
64.5
通讯作者：
Kuriyan, J
中科院分区：
文献类型：
--
作者：
Rosenberg, OS;Deindl, S;Kuriyan, J
Ca2+/钙调素依赖性蛋白激酶ii （CaMKII）是蛋白激酶中独特的十二聚体组装和对Ca2+的复杂反应。在1.8埃分辨率下测定了CaMKII的自抑制激酶结构域的晶体结构，揭示了一种意想不到的二聚体组织，其中钙调素响应的调节片段形成盘绕状结构，阻断肽和ATP与其他内在活性激酶结构域的结合。调节片段中的苏氨酸残基，当磷酸化使CaMKII钙调蛋白独立时，通过二聚体的组织与催化位点分开。这确保了初始激活严格依赖于Ca2+。激酶二聚体的结构，当与全酶的小角度x射线散射数据相结合时，表明失活的CaMKII形成紧密排列的自抑制组装，在激活后转化为松散连接和独立的激酶结构域簇。
Ca2+/calmodulin-dependent protein kinase-II (CaMKII) is unique among protein kinases for its dodecameric assembly and its complex response to Ca2+. The crystal structure of the autoinhibited kinase domain of CaMKII, determined at 1.8 angstrom resolution, reveals an unexpected dimeric organization in which the calmodulin-responsive regulatory segments form a coiled-coil strut that blocks peptide and ATP binding to the otherwise intrinsically active kinase domains. A threonine residue in the regulatory segment, which when phosphorylated renders CaMKII calmodulin independent, is held apart from the catalytic sites by the organization of the dimer. This ensures a strict Ca2+ dependence for initial activation. The structure of the kinase dimer, when combined with small-angle X-ray scattering data for the holoenzyme, suggests that inactive CaMKII forms tightly packed autoinhibited assemblies that convert upon activation into clusters of loosely tethered and independent kinase domains.