Work

Methotrexate Inhibits Proteolysis of Dihydrofolate Reductase by the N-end Rule Pathway

Year: 1995

Type: article

Abstract: The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. In eukaryotes, the N-end rule pathway is a ubiquitin-dependent, proteasome-based system that targets and processively degrades proteins bearing certain N-terminal residues. Arg-DHFR, a modified dihydrofolate reductase bearing an N-terminal arginine (destabilizing residue in the N-end rule), is short lived in ATP-supplemented reticulocyte extract. It is shown here that methotrexate, which is a folic acid analog and high affinity ligand of DHFR, inhibits the degradation but not ubiquitination of Arg-DHFR by the N-end rule pathway. The degradation of other N-end rule substrates is not affected by methotrexate. We discuss implications of these results for the mechanism of proteasome-mediated protein degradation.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.270.14.8172

Authors: Jennifer A. Johnston, Erica S. Johnson, Patrick R.H. Waller, Alexander Varshavsky

Institution: California Institute of Technology

Language: English

Topic: Ubiquitin and proteasome pathways

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430