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Prion Protein Folding Mechanism Revealed by Pulling Force Studies

Theresa Kriegler, Sven Lang, Luigi Notari, View ORCID ProfileTara Hessa
doi: https://doi.org/10.1101/2020.03.09.983510
Theresa Kriegler
1Department of Biochemistry and Biophysics Arrhenius Laboratories of Natural Sciences Stockholm University Svante Arrhenius väg 16C SE-10691 Stockholm, Sweden
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Sven Lang
2Department of Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany
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Luigi Notari
3Department of Clinical Neuroscience Therapeutic Immune Design Unit CMM, L8:02 Karolinska Institutet, Sweden
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Tara Hessa
1Department of Biochemistry and Biophysics Arrhenius Laboratories of Natural Sciences Stockholm University Svante Arrhenius väg 16C SE-10691 Stockholm, Sweden
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  • ORCID record for Tara Hessa
  • For correspondence: tara.hessa@dbb.su.se
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Abstract

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 09, 2020.
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Prion Protein Folding Mechanism Revealed by Pulling Force Studies
Theresa Kriegler, Sven Lang, Luigi Notari, Tara Hessa
bioRxiv 2020.03.09.983510; doi: https://doi.org/10.1101/2020.03.09.983510
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Prion Protein Folding Mechanism Revealed by Pulling Force Studies
Theresa Kriegler, Sven Lang, Luigi Notari, Tara Hessa
bioRxiv 2020.03.09.983510; doi: https://doi.org/10.1101/2020.03.09.983510

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