| Structural highlights
Function
MNL1_YEAST Alpha-1,2-specific exomannosidase involved in endoplasmic reticulum-associated degradation (ERAD). Delivers misfolded glycoproteins to proteasomes. Forms a complex with PDI1 to process unfolded protein-bound Man8GlcNAc2 oligosaccharides to Man7GlcNAc2, promoting degradation in unfolded protein response.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Misfolded glycoproteins in the endoplasmic reticulum (ER) lumen are translocated into the cytosol and degraded by the proteasome, a conserved process called ER-associated protein degradation (ERAD). In S. cerevisiae, the glycan of these proteins is trimmed by the luminal mannosidase Mnl1 (Htm1) to generate a signal that triggers degradation. Curiously, Mnl1 is permanently associated with protein disulfide isomerase (Pdi1). Here, we have used cryo-electron microscopy, biochemical, and in vivo experiments to clarify how this complex initiates ERAD. The Mnl1-Pdi1 complex first de-mannosylates misfolded, globular proteins that are recognized through a C-terminal domain (CTD) of Mnl1; Pdi1 causes the CTD to ignore completely unfolded polypeptides. The disulfides of these globular proteins are then reduced by the Pdi1 component of the complex, generating unfolded polypeptides that can be translocated across the membrane. Mnl1 blocks the canonical oxidative function of Pdi1, but allows it to function as the elusive disulfide reductase in ERAD.
Initiation of ERAD by the bifunctional complex of Mnl1 mannosidase and protein disulfide isomerase.,Zhao D, Wu X, Rapoport TA bioRxiv [Preprint]. 2024 Oct 17:2024.10.17.618908. doi: , 10.1101/2024.10.17.618908. PMID:39464000[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nakatsukasa K, Nishikawa S, Hosokawa N, Nagata K, Endo T. Mnl1p, an alpha -mannosidase-like protein in yeast Saccharomyces cerevisiae, is required for endoplasmic reticulum-associated degradation of glycoproteins. J Biol Chem. 2001 Mar 23;276(12):8635-8. PMID:11254655 doi:10.1074/jbc.C100023200
- ↑ Jakob CA, Bodmer D, Spirig U, Battig P, Marcil A, Dignard D, Bergeron JJ, Thomas DY, Aebi M. Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast. EMBO Rep. 2001 May;2(5):423-30. PMID:11375935 doi:10.1093/embo-reports/kve089
- ↑ Vashist S, Ng DT. Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J Cell Biol. 2004 Apr;165(1):41-52. PMID:15078901 doi:10.1083/jcb.200309132
- ↑ Gnann A, Riordan JR, Wolf DH. Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast. Mol Biol Cell. 2004 Sep;15(9):4125-35. PMID:15215312 doi:10.1091/mbc.e04-01-0024
- ↑ Spear ED, Ng DT. Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation. J Cell Biol. 2005 Apr 11;169(1):73-82. PMID:15809311 doi:10.1083/jcb.200411136
- ↑ Clerc S, Hirsch C, Oggier DM, Deprez P, Jakob C, Sommer T, Aebi M. Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J Cell Biol. 2009 Jan 12;184(1):159-72. doi: 10.1083/jcb.200809198. Epub 2009 Jan, 5. PMID:19124653 doi:https://dx.doi.org/10.1083/jcb.200809198
- ↑ Gauss R, Kanehara K, Carvalho P, Ng DT, Aebi M. A complex of Pdi1p and the mannosidase Htm1p initiates clearance of unfolded glycoproteins from the endoplasmic reticulum. Mol Cell. 2011 Jun 24;42(6):782-93. doi: 10.1016/j.molcel.2011.04.027. PMID:21700223 doi:https://dx.doi.org/10.1016/j.molcel.2011.04.027
- ↑ Zhao D, Wu X, Rapoport TA. Initiation of ERAD by the bifunctional complex of Mnl1 mannosidase and protein disulfide isomerase. bioRxiv [Preprint]. 2024 Oct 17:2024.10.17.618908. PMID:39464000 doi:10.1101/2024.10.17.618908
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