Identification and characterization of Yos9 as a sugar sensor of misfolded proteins


How misfolded forms are recognized and distinguished from the myriad of folding substrates represents a fascinating problem in discrimination. Cells must maintain a balance between overly promiscuous destruction of slow-folding proteins, while preventing escape of toxic forms. For most luminal proteins, this discrimination depends not only on the folding status of a polypeptide, but also on its glycosylation state.

We, and others concurrently, identified the conserved luminal protein Yos9 as the lectin sensor responsible for probing the glycosylation state of misfolded proteins. This allowed us, in a series of papers, to work out the elaborate mechanism used to correctly mark and degrade terminally misfolded proteins. This strategy of marking potential substrates by a sugar modification and decoding the signal in a second recognition event provides a proofreading mechanism for enhancing substrate specificity. We are now recapitulating this modification and recognition cascade in vitro from purified components. I am particularly excited about this work as it represents a terrific opportunity to provide our most in-depth structural and mechanistic understanding to the fascinating question of how the ER tells right from wrong.