Malevanets, A;
Chong, PA;
Hansen, DF;
Rizk, P;
Sun, Y;
Lin, H;
Muhandiram, R;
... Wodak, SJ; + view all
(2017)
Interplay of buried histidine protonation and protein stability in prion misfolding.
Scientific Reports
, 7
, Article 882. 10.1038/s41598-017-00954-7.
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Abstract
Misofolding of mammalian prion proteins (PrP) is believed to be the cause of a group of rare and fatal neurodegenerative diseases. Despite intense scrutiny however, the mechanism of the misfolding reaction remains unclear. We perform nuclear Magnetic Resonance and thermodynamic stability measurements on the C-terminal domains (residues 90–231) of two PrP variants exhibiting different pH-induced susceptibilities to aggregation: the susceptible hamster prion (GHaPrP) and its less susceptible rabbit homolog (RaPrP). The pKa of histidines in these domains are determined from titration experiments, and proton-exchange rates are measured at pH 5 and pH 7. A single buried highly conserved histidine, H187/H186 in GHaPrP/RaPrP, exhibited a markedly down shifted pKa ~5 for both proteins. However, noticeably larger pH-induced shifts in exchange rates occur for GHaPrP versus RaPrP. Analysis of the data indicates that protonation of the buried histidine destabilizes both PrP variants, but produces a more drastic effect in the less stable GHaPrP. This interpretation is supported by urea denaturation experiments performed on both PrP variants at neutral and low pH, and correlates with the difference in disease susceptibility of the two species, as expected from the documented linkage between destabilization of the folded state and formation of misfolded and aggregated species.
| Type: | Article |
|---|---|
| Title: | Interplay of buried histidine protonation and protein stability in prion misfolding |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41598-017-00954-7 |
| Publisher version: | http://dx.doi.org/10.1038/s41598-017-00954-7 |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, GROUP HYDROGEN-EXCHANGE, NMR STRUCTURES, MOLECULAR-MECHANISM, DOMAIN PRP(121-231), SCRAPIE, HAMSTER, PH, RESIDUES, DYNAMICS, DISEASE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1551947 |
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