Altered activity, social behavior, and spatial memory in mice lacking the NTAN1p amidase and the asparagine branch of the N-end rule pathway

The N-end rule relates the in vivo half-life of a protein to the identity o f its N-terminal residue. N-terminal asparagine and glutamine are tertiary destabilizing residues, in that they are enzymatically deamidated to yield secondary destabilizing residues aspartate and glutamate, which are conjuga ted to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3 alpha, the E3 component o f the ubiquitin-proteasome-dependent N-end rule pathway. We describe the co nstruction and analysis of mouse strains lacking the asparagine-specific N- terminal amidase (Nt(N)-amidase), encoded by the Ntan1 gene. In wild-type e mbryos, Ntan1 was strongly expressed in the branchial arches and in the tai l and limb buds. The Ntan1(-/-) mouse strains lacked the Nt(N)-amidase acti vity but retained glutamine-specific Nt(Q)-amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-e nd rule substrates, only those bearing N-terminal asparagine became long-li ved in Ntan1(-/-) fibroblasts,;The Ntan1(-/-) mice were fertile and outward ly normal but differed from their congenic wild-type counterparts in sponta neous activity, spatial memory, and a socially conditioned exploratory phen otype that has not been previously described with other mouse strains.