Characterization of nectin processing mediated by presenilin-dependent γ-secretase.

Characterization of nectin processing mediated by presenilin-dependent γ-secretase.
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DOI:
10.1111/j.1471-4159.2011.07479.x
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发表时间:
2011-12
影响因子:
4.7
通讯作者:
Lim ST
Lim ST
中科院分区:
医学2区
文献类型:
--
作者:
Kim J;Chang A;Dudak A;Federoff HJ;Lim ST

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Nectins play an important role in forming various intercellular junctions including synapses. This role is regulated by several secretases present at intercellular junctions. We have investigated presenilin (PS)-dependent secretase mediated processing of nectins in PS1 KO cells and primary hippocampal neurons. The loss of PS1/gamma-secretase activity delayed the processing of nectin-1 and caused the accumulation of its full-length and C-terminal fragments. Overexpression of PS2 in PS1 KO cells compensated for the loss of PS1, suggesting that PS2 also has the ability to regulate nectin-1 processing. In mouse brain slices, a pronounced increase in levels of 30 and 24 kDa CTFs in response to chemical LTP was observed. The mouse brain synaptosomal fractionation study indicated that nectin-1 localized to postsynaptic and preferentially presynaptic membranes and that shedding occurs in both compartments. These data suggest that nectin-1 shedding and PS-dependent intramembrane cleavage occur at synapses, and is a regulated event during conditions of synaptic plasticity in the brain. Point mutation analysis identified several residues within the transmembrane domain that play a critical role in the positioning of cleavage sites by ectodomain sheddases. Nectin-3, which forms hetero-trans-dimers with nectin-1, also undergoes intramembrane cleavage mediated by PS1/γ-secretase, suggesting that PS1/γ-secreatse activity regulates synapse formation and remodeling by nectin processing.
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