Evolutionary adaptation of the folding pathway for secretability

Abstract

Secretory preproteins of the Sec pathway bear signal peptides and are targeted 34 post-translationally to cross the plasma membrane or ER through 35 translocases. After translocation and signal peptide cleavage, mature domains 36 fold to native states in the bacterial periplasm or after further trafficking. 37 During cytoplasmic transit, mature domains must remain non-folded for 38 translocase recognition and translocation. Here, we sought the structural basis 39 for the delayed folding mechanism of mature domains and how this is 40 regulated by signal peptides. To address this, we compared how evolution 41 diversified a periplasmic peptidyl-prolyl isomerase PpiA mature domain from 42 its structural twin cytoplasmic PpiB.