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Molecular and Cellular Biology, June 2000, p. 4135-4148, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Altered Activity, Social Behavior, and Spatial Memory in Mice Lacking the NTAN1p Amidase and the Asparagine Branch of the N-End Rule Pathway

Yong Tae Kwon,1 Seth A. Balogh,2 Ilia V. Davydov,1 Anna S. Kashina,1 Jeong Kyo Yoon,1 Youming Xie,1 Arti Gaur,1,dagger Lynn Hyde,2,Dagger Victor H. Denenberg,2,3 and Alexander Varshavsky1,*

Division of Biology, California Institute of Technology, Pasadena, California 91125,1 and Biobehavioral Sciences Graduate Program2 and Department of Psychology,3 University of Connecticut, Storrs, Connecticut 06269-4154

Received 30 December 1999/Returned for modification 28 February 2000/Accepted 8 March 2000

The N-end rule relates the in vivo half-life of a protein to the identity of 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 conjugated to arginine, a primary destabilizing residue. N-terminal arginine of a substrate protein is bound by the Ubr1-encoded E3alpha , the E3 component of the ubiquitin-proteasome-dependent N-end rule pathway. We describe the construction and analysis of mouse strains lacking the asparagine-specific N-terminal amidase (NtN-amidase), encoded by the Ntan1 gene. In wild-type embryos, Ntan1 was strongly expressed in the branchial arches and in the tail and limb buds. The Ntan1-/- mouse strains lacked the NtN-amidase activity but retained glutamine-specific NtQ-amidase, indicating that the two enzymes are encoded by different genes. Among the normally short-lived N-end rule substrates, only those bearing N-terminal asparagine became long-lived in Ntan1-/- fibroblasts. The Ntan1-/- mice were fertile and outwardly normal but differed from their congenic wild-type counterparts in spontaneous activity, spatial memory, and a socially conditioned exploratory phenotype that has not been previously described with other mouse strains.

* Corresponding author. Mailing address: Alexander Varshavsky, Division of Biology, 147-75, Caltech, 1200 East California Blvd., Pasadena, CA 91125. Phone: (626) 395-3785. Fax: (626) 440-9821. E-mail: avarsh{at}caltech.edu.

dagger Present address: Institute for Genetics, University of Cologne, Cologne D-50931, Germany.

Dagger Present address: Department of Pediatrics and Psychiatry, University of Colorado School of Medicine, Denver, CO 80262.

Molecular and Cellular Biology, June 2000, p. 4135-4148, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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