title: Futile protein folding cycles in the ER are terminated by the unfolded protein O-mannosylation pathway.
abstract: Newly synthesized polypeptides fold and assemble with assistance from protein chaperones. Full maturation can take multiple attempts, exchanging chaperones at each round. Improperly folded molecules must exit folding cycles and be degraded. In the endoplasmic reticulum (ER), prolonged substrate cycling is detrimental because it expends chaperone and energy resources and increases toxic reactive oxygen species. In budding yeast, we found that unfolded protein O-mannosylation terminated failed folding attempts through the Pmt1/Pmt2 complex. O-mannosylation incapacitated target molecule folding and removed them from folding cycles by reducing engagement with the Kar2 chaperone. In an in vitro protein refolding assay, the modification intrinsically and irreversibly disabled the folding potential of the substrate. Thus, protein folding termination can involve a covalent glycosylation event.
authors.affiliation: Temasek Life Sciences Laboratory, National University of Singapore, Singapore.
authors.forename: Chengchao
authors.initials: C
authors.lastname: Xu
authors.forename: Songyu
authors.initials: S
authors.lastname: Wang
authors.forename: Guillaume
authors.initials: G
authors.lastname: Thibault
authors.forename: Davis T W
authors.initials: DT
authors.lastname: Ng
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D006031:Glycosylation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism*; D008364:Mannosyltransferases / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D005656:Fungal Proteins; D018840:HSP70 Heat-Shock Proteins; C060153:KAR2 protein, yeast; D049452:Green Fluorescent Proteins; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase; D008358:Mannose