自磷酸化的 CaMKIIalpha 作为支架将蛋白酶体募集到树突棘。

Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines.

机构信息

The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences and Biology, Massachusetts Institute of Technology, Cambridge, 02139, USA.

出版信息

Cell. 2010 Feb 19;140(4):567-78. doi: 10.1016/j.cell.2010.01.024.

DOI:10.1016/j.cell.2010.01.024

PMID:20178748

Abstract

The molecular mechanisms regulating the ubiquitin proteasome system (UPS) at synapses are poorly understood. We report that CaMKIIalpha-an abundant postsynaptic protein kinase-mediates the activity-dependent recruitment of proteasomes to dendritic spines in hippocampal neurons. CaMKIIalpha is biochemically associated with proteasomes in the brain. CaMKIIalpha translocation to synapses is required for activity-induced proteasome accumulation in spines, and is sufficient to redistribute proteasomes to postsynaptic sites. CaMKIIalpha autophosphorylation enhances its binding to proteasomes and promotes proteasome recruitment to spines. In addition to this structural role, CaMKIIalpha stimulates proteasome activity by phosphorylating proteasome subunit Rpt6 on Serine 120. However, CaMKIIalpha translocation, but not its kinase activity, is required for activity-dependent degradation of polyubiquitinated proteins in spines. Our findings reveal a scaffolding role of postsynaptic CaMKIIalpha in activity-dependent proteasome redistribution, which is commensurate with the great abundance of CaMKIIalpha in synapses.

摘要

调控突触泛素蛋白酶体系统（UPS）的分子机制还知之甚少。我们报告说，CaMKIIalpha-一种丰富的突触后蛋白激酶-介导了蛋白酶体在海马神经元树突棘中的活性依赖性募集。CaMKIIalpha 在大脑中与蛋白酶体在生化上相关。CaMKIIalpha 向突触的易位是活性诱导的蛋白酶体在棘突中积累所必需的，并且足以将蛋白酶体重新分布到突触后位点。CaMKIIalpha 的自身磷酸化增强了其与蛋白酶体的结合，并促进了蛋白酶体向棘突的募集。除了这种结构作用外，CaMKIIalpha 通过磷酸化蛋白酶体亚基 Rpt6 的丝氨酸 120 来刺激蛋白酶体的活性。然而，对于活性依赖性的多泛素化蛋白在棘突中的降解，CaMKIIalpha 的易位而不是其激酶活性是必需的。我们的发现揭示了突触后 CaMKIIalpha 在活性依赖性蛋白酶体重分布中的支架作用，这与突触中 CaMKIIalpha 的巨大丰度相一致。