Futile Protein Folding Cycles in the ER Are Terminated by the Unfolded Protein O-Mannosylation Pathway

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Science  24 May 2013:
Vol. 340, Issue 6135, pp. 978-981
DOI: 10.1126/science.1234055

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Folding Too Slow, Off You Go

One of the major questions of chaperone-assisted protein-folding pathways is how substrates that fail to fold avoid futile folding cycles. Xu et al. (p. 978; see the Perspective by Kleizen and Braakman) developed a model to examine a folding-competent protein that nevertheless fails to fold within the endoplasmic reticulum. Under these circumstances, the unfolded protein was subject to an unusual glycosylation, O-mannosylation, which appeared to terminate folding of the unfinished molecules. Eliminating O-mannosylation allowed the protein to fold completely.


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.

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