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ER translocation of suboptimal targeting sequences depends on Sec61β/Sbh1 and its phosphorylation

Barbieri, G.; Simon, J.; Lupusella, C. R.; Pereira, F.; Elia, F.; Meyer, H.; Schuldiner, M.; Hanes, S. D.; Nguyen, D.; Helms, V.; Romisch, K.

2022-05-19 biochemistry
10.1101/2022.05.18.492448 bioRxiv
Show abstract

The endoplasmic reticulum (ER) protein translocation channel subunit Sec61{beta}/Sbh1 is non-essential, but contains multiple phosphorylation sites suggesting a regulatory role in ER protein import. We show here that mutating two N-terminal, proline-flanked, phosphorylation sites in the Sbh1 cytosolic domain phenocopies the temperature-sensitivity of a yeast strain lacking SBH1/SBH2, and results in reduced translocation into the ER of an Sbh1-dependent substrate, Gls1. In a microscopic screen we show that about 12% of GFP-tagged secretory proteins depend on Sbh1 for translocation. Sbh1-dependent proteins have targeting sequences with less pronounced hydrophobicity and often no or an inverse charge bias. A subset of these proteins was dependent on N-terminal phosphorylation of Sbh1 and on the phospho-S/T-specific proline isomerase Ess1 (PIN1 in mammals) for ER import. We conclude that Sbh1 promotes ER translocation of substrates with suboptimal targeting sequences and that its activity is regulated by a conformational change induced by N-terminal phosphorylation.

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