title: Characterization of nectin processing mediated by presenilin-dependent γ-secretase.
abstract: 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/γ-secretase activity delayed the processing of nectin-1 and caused the accumulation of its full-length and C-terminal fragments. Over-expression 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 C-terminal fragments in response to chemical long-term potentiation was observed. The mouse brain synaptosomal fractionation study indicated that nectin-1 localized to post-synaptic and preferentially pre-synaptic 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.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, NW, Washington, District of Columbia, USA.
authors.forename: Jinsook
authors.initials: J
authors.lastname: Kim
authors.forename: Allison
authors.initials: A
authors.lastname: Chang
authors.forename: Amanda
authors.initials: A
authors.lastname: Dudak
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
authors.forename: Seung T
authors.initials: ST
authors.lastname: Lim
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D000075983:Nectins; D009924:Organ Culture Techniques; D017354:Point Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053766:Presenilin-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619014:NECTIN3 protein, human; C000619015:Nectin1 protein, mouse; C000619017:Nectin3 protein, mouse; D000075983:Nectins; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; D053829:Amyloid Precursor Protein Secretases