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Pathological mutations H187R and E196K facilitate subdomain separation and prion protein conversion by destabilization of the native structure

2014; Wiley; Volume: 29; Issue: 3 Linguagem: Inglês

10.1096/fj.14-255646

1530-6860

San Hadži, Andrej Ondračka, Roman Jerala, Iva Hafner‐Bratkovič,

Enzyme Structure and Function

The FASEB JournalVolume 29, Issue 3 p. 882-893 Research CommunicationFree to Read Pathological mutations H187R and E196K facilitate subdomain separation and prion protein conversion by destabilization of the native structure San Hadži, San Hadži Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia Current affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium. Current affiliation: Department of Physical Chemistry, Faculty for Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.Search for more papers by this authorAndrej Ondračka, Andrej Ondračka Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia Current affiliation: The Rockefeller University, New York, New York, USA.Search for more papers by this authorRoman Jerala, Roman Jerala Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia EN-FIST Centre of Excellence, Ljubljana, SloveniaSearch for more papers by this authorIva Hafner-Bratkovič, Corresponding Author Iva Hafner-Bratkovič [email protected] Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia EN-FIST Centre of Excellence, Ljubljana, SloveniaCorrespondence: Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia. E-mail: [email protected]Search for more papers by this author San Hadži, San Hadži Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia Current affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium. Current affiliation: Department of Physical Chemistry, Faculty for Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.Search for more papers by this authorAndrej Ondračka, Andrej Ondračka Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia Current affiliation: The Rockefeller University, New York, New York, USA.Search for more papers by this authorRoman Jerala, Roman Jerala Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia EN-FIST Centre of Excellence, Ljubljana, SloveniaSearch for more papers by this authorIva Hafner-Bratkovič, Corresponding Author Iva Hafner-Bratkovič [email protected] Department of Biotechnology, National Institute of Chemistry, Ljubljana, Slovenia EN-FIST Centre of Excellence, Ljubljana, SloveniaCorrespondence: Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia. E-mail: [email protected]Search for more papers by this author First published: 21 November 2014 https://doi.org/10.1096/fj.14-255646Citations: 13 Current affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium. Current affiliation: Department of Physical Chemistry, Faculty for Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia. This article includes supplemental data. Please visit http://www.fasebj.org to obtain this information. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract The mechanism of prion protein (PrP) conversion, the key event in prion diseases, is still not understood. We investigated how perturbations of interactions between the subdomains β1-α1-β2 and α2-α3 affect PrP conversion. In vitro fibrillization and biophysical methods were used to relate mouse PrP conversion kinetics to thermodynamic stability. We show that pathologic mutations H187R and E196K destabilize PrP (by 3.2 and 1.1 kJ/mol, respectively, at pH 7) and accelerate fibrillization. At acidic pH, the major contribution to the destabilization of PrP comes from the protonation of histidine 187 because its replacement by tyrosine led to more stable protein (by 4.2 kJ/mol at pH 4) with slower fibrillization. Furthermore, we show that the introduction of a novel histidine residue into the subdomain interface (F198H) acts as a pH-inducible switch that promotes conversion upon histidine protonation, whereas this effect is not observed when His residue is introduced at the protein surface (Y155H). We observed a strong correlation between the stability of native structure and kinetics of fibrillization of PrP variants. Our results show that pathologic mutations promote subdomain separation and suggest that stabilization of the native structure might be a viable strategy for the development of novel therapeutics for prion diseases.—Hadži, S., Ondračka, A., Jerala, R., and Hafner-Bratkovič, I., Pathological mutations H187R and E196K facilitate subdomain separation and prion protein conversion by destabilization of the native structure. FASEB J. 29, 882–893 (2015). www.fasebj.org REFERENCES 1Chiti, F., and Dobson, C. M. (2006) Protein misfolding, functional amyloid, and human disease. Annu. Rev. 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