Ubiquitin carboxyl-terminal hydrolase 46 (USP46) is a specialized cysteine protease with a predicted molecular weight of 42 kDa. USP46 is a member of the peptidase C19 family and USP12/USP46 subfamily, and the human protein shares 100% amino acid sequence identity with its mouse ortholog. Like USP1 and USP12, USP46 lacks appreciable activity in the absence of its co-activator UAF1. Addition of UAF1 increases the in vitro activity of USP46 10-fold or more. Biologically, USP46 has been implicated in the regulation of Alpha-Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs). USP46 is able to deubiquitinate AMPARs both in vivo and in vitro, and by regulating the status of AMPAR ubiquitination and turnover, this deubiquitinase may play an important role in synaptic plasticity and brain function. Recombinant USP46 contains a C-terminal 6-His tag. Recombinant UAF1 also contains a C-terminal 6-His tag. The assembled complex contains 25 µg USP46 and 45 µg UAF1, resulting in a 1:1 stoichiometry.
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