PT  - JOURNAL ARTICLE
AU  - Sha Sun
AU  - Xia Li
AU  - Malaiyalam Mariappan
TI  - Signal Sequences Encode Information for Protein Folding in the Endoplasmic Reticulum
AID  - 10.1101/2020.06.04.133884
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.04.133884
4099  - http://biorxiv.org/content/early/2020/06/05/2020.06.04.133884.short
4100  - http://biorxiv.org/content/early/2020/06/05/2020.06.04.133884.full
AB  - Roughly one-third of newly synthesized proteins enter into the endoplasmic reticulum (ER) via the Sec61 translocon. It is unclear how nascent chains bind correct chaperones and properly fold upon entering the ER lumen. We find that signal sequences harbor information to recruit specific chaperones for protein folding in the ER. Using a substrate-trapping proteomic approach, we identify that marginally hydrophobic signal sequences are transiently clogged at the Sec61 translocon, which recruits BiP chaperone through Sec63 to bind onto nascent chains. Surprisingly, this privileged BiP binding not only releases clogged nascent chains into the ER lumen but also prevent inappropriate interactions and promotes folding and maturation. Signal sequence swapping bypasses BiP-dependent unclogging and translocation, but the translocated nascent chain is terminally misfolded after binding the wrong chaperone in the ER lumen. Thus, signal sequence-dependent chaperone recruitment explains why signal sequences are paradoxically diverse and use multiple protein translocation pathways in cells.Competing Interest StatementThe authors have declared no competing interest.