Structural highlights
Function
[NGLY1_MOUSE] Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Cleaves the beta-aspartyl-glucosamine (GlcNAc) of the glycan and the amide side chain of Asn, converting Asn to Asp. Prefers proteins containing high-mannose over those bearing complex type oligosaccharides. Can recognize misfolded proteins in the endoplasmic reticulum that are exported to the cytosol to be destroyed and deglycosylate them, while it has no activity toward native proteins. Deglycosylation is a prerequisite for subsequent proteasome-mediated degradation of some, but not all, misfolded glycoproteins.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Studies on peptide:N-glycanase-p97 interaction suggest that p97 phosphorylation modulates endoplasmic reticulum-associated degradation.,Zhao G, Zhou X, Wang L, Li G, Schindelin H, Lennarz WJ Proc Natl Acad Sci U S A. 2007 May 22;104(21):8785-90. Epub 2007 May 11. PMID:17496150[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Park H, Suzuki T, Lennarz WJ. Identification of proteins that interact with mammalian peptide:N-glycanase and implicate this hydrolase in the proteasome-dependent pathway for protein degradation. Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11163-8. Epub 2001 Sep 18. PMID:11562482 doi:http://dx.doi.org/10.1073/pnas.201393498
- ↑ Hirsch C, Blom D, Ploegh HL. A role for N-glycanase in the cytosolic turnover of glycoproteins. EMBO J. 2003 Mar 3;22(5):1036-46. PMID:12606569 doi:http://dx.doi.org/10.1093/emboj/cdg107
- ↑ Katiyar S, Li G, Lennarz WJ. A complex between peptide:N-glycanase and two proteasome-linked proteins suggests a mechanism for the degradation of misfolded glycoproteins. Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13774-9. Epub 2004 Sep 9. PMID:15358861 doi:http://dx.doi.org/10.1073/pnas.0405663101
- ↑ Zhao G, Zhou X, Wang L, Li G, Schindelin H, Lennarz WJ. Studies on peptide:N-glycanase-p97 interaction suggest that p97 phosphorylation modulates endoplasmic reticulum-associated degradation. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8785-90. Epub 2007 May 11. PMID:17496150
