Studies on peptide:N-glycanase-p97 interaction suggest that p97 phosphorylation modulates endoplasmic reticulum-associated degradation.

During endoplasmic reticulum-associated degradation, the multifunctional AAA ATPase p97 is part of a protein degradation complex. p97 associates via its N-terminal domain with various cofactors to recruit ubiquitinated substrates. It also interacts with alternative substrate-processing cofactors, such as Ufd2, Ufd3, and peptide:N-glycanase (PNGase) in higher eukaryotes. These cofactors determine different ...
fates of the substrates and they all bind outside of the N-terminal domain of p97. Here, we describe a cofactor-binding motif of p97 contained within the last 10 amino acid residues of the C terminus, which is both necessary and sufficient to mediate interactions of p97 with PNGase and Ufd3. The crystal structure of the N-terminal domain of PNGase in complex with this motif provides detailed insight into the interaction between p97 and its substrate-processing cofactors. Phosphorylation of p97's highly conserved penultimate tyrosine residue, which is the main phosphorylation site during T cell receptor stimulation, completely blocks binding of either PNGase or Ufd3 to p97. This observation suggests that phosphorylation of this residue modulates endoplasmic reticulum-associated protein degradation activity by discharging substrate-processing cofactors.
Mesh Terms:
Adenosine Triphosphatases, Amino Acid Motifs, Animals, Crystallography, X-Ray, DNA, Endoplasmic Reticulum, Mice, Models, Molecular, Nuclear Proteins, Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase, Phosphorylation, Phosphotyrosine, Protein Binding, Protein Structure, Quaternary, Protein Structure, Tertiary
Proc. Natl. Acad. Sci. U.S.A.
Date: May. 22, 2007
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