RT Journal Article
SR Electronic
T1 Prion Protein Folding Mechanism Revealed by Pulling Force Studies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.09.983510
DO 10.1101/2020.03.09.983510
A1 Kriegler, Theresa
A1 Lang, Sven
A1 Notari, Luigi
A1 Hessa, Tara
YR 2020
UL http://biorxiv.org/content/early/2020/03/09/2020.03.09.983510.abstract
AB The mammalian prion protein (PrP) engages with the ribosome-Sec61 translocation channel complex to generate different topological variants that are either physiological, or involved in neurodegenerative diseases. Here, we describe cotranslational folding and translocation mechanisms of PrP coupled to a Xbp1-based arrest peptide (AP) as folding sensor, to measure forces acting on PrP nascent chain. Our data reveal two main pulling events followed by a minor third one exerted on the nascent chains during their translocation.Using those force landscapes, we show that a specific sequence within an intrinsically disordered region, containing a polybasic and glycine-proline rich residues, modulates the second pulling event by interacting with TRAP complex. This work also delineates the sequence of events involved in generation of PrP toxic transmembrane topologies during its synthesis. Our results shed new insight into the folding of such topological complex protein, where marginal pulling by the signal sequence, together with the downstream sequence in the mature domain, primarily drives an overall inefficient translocation resulting in the nascent chain to adopt other topologies.