Brigidi G Stefano, Santyr Brendan, Shimell Jordan, Jovellar Blair, Bamji Shernaz X
Department of Cellular and Physiological Sciences, and the Djavad Mowafaghian Center for Brain Health, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada, V6T-1Z3.
Nat Commun. 2015 Sep 3;6:8200. doi: 10.1038/ncomms9200.
Synaptic plasticity is mediated by the dynamic localization of proteins to and from synapses. This is controlled, in part, through activity-induced palmitoylation of synaptic proteins. Here we report that the ability of the palmitoyl-acyl transferase, DHHC5, to palmitoylate substrates in an activity-dependent manner is dependent on changes in its subcellular localization. Under basal conditions, DHHC5 is bound to PSD-95 and Fyn kinase, and is stabilized at the synaptic membrane through Fyn-mediated phosphorylation of a tyrosine residue within the endocytic motif of DHHC5. In contrast, DHHC5's substrate, δ-catenin, is highly localized to dendritic shafts, resulting in the segregation of the enzyme/substrate pair. Neuronal activity disrupts DHHC5/PSD-95/Fyn kinase complexes, enhancing DHHC5 endocytosis, its translocation to dendritic shafts and its association with δ-catenin. Following DHHC5-mediated palmitoylation of δ-catenin, DHHC5 and δ-catenin are trafficked together back into spines where δ-catenin increases cadherin stabilization and recruitment of AMPA receptors to the synaptic membrane.
突触可塑性是由蛋白质往返突触的动态定位介导的。这部分是通过活性诱导的突触蛋白棕榈酰化来控制的。在这里，我们报告棕榈酰酰基转移酶DHHC5以活性依赖方式棕榈酰化底物的能力取决于其亚细胞定位的变化。在基础条件下，DHHC5与PSD-95和Fyn激酶结合，并通过Fyn介导的DHHC5内吞基序中酪氨酸残基的磷酸化而稳定在突触膜上。相反，DHHC5的底物δ-连环蛋白高度定位于树突轴，导致酶/底物对的分离。神经元活动破坏DHHC5/PSD-95/Fyn激酶复合物，增强DHHC5的内吞作用、其向树突轴的转运以及与δ-连环蛋白的结合。在DHHC5介导的δ-连环蛋白棕榈酰化之后，DHHC5和δ-连环蛋白一起被运回棘突，在那里δ-连环蛋白增加钙黏蛋白的稳定性并将AMPA受体招募到突触膜。
