Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly.
Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly.
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DOI：
10.1016/j.celrep.2021.110168
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发表时间：
2021-12-28
期刊：
影响因子：
8.8
通讯作者：
Reichow SL
中科院分区：
文献类型：
--
作者：
Buonarati OR;Miller AP;Coultrap SJ;Bayer KU;Reichow SL
神经元CaMKII全酶（α和β亚型）使学习和记忆的分子信号计算成为可能，但也介导兴奋性毒性神经元死亡。在这里，我们使用单粒子电子显微镜（EM）结合生化和活细胞成像研究，对这些信号装置进行了比较分析。在基态下，这两种同工异构体主要以12-mers的形式聚集（但β同工异构体也以14-mers甚至16-mers的形式聚集）。CaMKIIα和β异构体采用扩展激活状态的集合（平均半径分别为12.6 nm和16.8 nm），其特征是与不同功能特性相关的多个瞬时全酶内和全酶间相互作用。CaMKIIβ的扩展状态允许直接解析全酶激酶结构域二聚体。这些二聚体可以使钙调素协同激活，这在两种同工异构体中都观察到。在体外和神经元中，由全酶激酶结构域二聚化介导的高阶CaMKII聚类在基底和兴奋性毒性诱导的簇中都减少了β异构体。CaMKII全酶使神经元信号计算成为可能。在神经元α和β亚型的比较结构-功能分析中，Buonarati等人发现全酶内的激酶结构域二聚体能够在全酶亚型和全酶间相互作用中实现协同激活机制，从而在缺血条件下形成高阶聚集体。
Neuronal CaMKII holoenzymes (α and β isoforms) enable molecular signal computation underlying learning and memory but also mediate excitotoxic neuronal death. Here, we provide a comparative analysis of these signaling devices, using single-particle electron microscopy (EM) in combination with biochemical and live-cell imaging studies. In the basal state, both isoforms assemble mainly as 12-mers (but also 14-mers and even 16-mers for the β isoform). CaMKIIα and β isoforms adopt an ensemble of extended activatable states (with average radius of 12.6 versus 16.8 nm, respectively), characterized by multiple transient intra- and inter-holoenzyme interactions associated with distinct functional properties. The extended state of CaMKIIβ allows direct resolution of intra-holoenzyme kinase domain dimers. These dimers could enable cooperative activation by calmodulin, which is observed for both isoforms. High-order CaMKII clustering mediated by inter-holoenzyme kinase domain dimerization is reduced for the β isoform for both basal and excitotoxicity-induced clusters, both in vitro and in neurons. The CaMKII holoenzyme enables neuronal signal computation. In a comparative structure-function analysis of the neuronal α and β isoforms, Buonarati et al. find evidence for kinase domain dimers within the holoenzyme that enable a cooperative activation mechanism in both isoforms and inter-holoenzyme interactions that enable high-order aggregate formation under ischemic conditions.
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影响因子：
8.2
作者：
Coultrap, Steven J.;Vest, Rebekah S.;Ashpole, Nicole M.;Hudmon, Andy;Bayer, K. Ulrich
通讯作者：
Bayer, K. Ulrich
影响因子：
56.9
作者：
De Koninck, P;Schulman, H
通讯作者：
Schulman, H
DOI：
10.1016/s0169-328x(99)00131-x
发表时间：
1999-06-18
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Bayer, KU;Löhler, J;Harbers, K
通讯作者：
Harbers, K
影响因子：
16.2
作者：
Barria, A;Malinow, R
通讯作者：
Malinow, R
影响因子：
7.2
作者：
Bhattacharyya, Moitrayee;Karandur, Deepti;Kuriyan, John
通讯作者：
Kuriyan, John