TY - JOUR
T1 - Structural determinants in prion protein folding and stability
AU - Benetti, Federico
AU - Biarnés, Xevi
AU - Attanasio, Francesco
AU - Giachin, Gabriele
AU - Rizzarelli, Enrico
AU - Legname, Giuseppe
N1 - Funding Information:
E.R. and G.L. gratefully acknowledge MIUR (Italian Ministry of Education, University and Research) for partially supporting this work through the PRIN 2010-2011 Program ( 2010M2JART_001 ). X.B. acknowledges financial support from the Government of Catalonia (AGAUR) through a Beatriu de Pinós fellowship ( BP-A-2007 ). This work was supported by the European Union's Seventh Framework Programme ( FP7/2007–2013 ) under grant agreement number 222887—the PRIORITY project to G.L. The authors wish to thank Alessandro Laio for extensive discussions on the manuscript.
Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.
PY - 2014/11/11
Y1 - 2014/11/11
N2 - Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases, involving post-translational modifications of the cellular prion protein. Epidemiological studies on Creutzfeldt-Jakob disease, a prototype prion disorder, show a majority of cases being sporadic, while the remaining occurrences are either genetic or iatrogenic. The molecular mechanisms by which PrPC is converted into its pathological isoform have not yet been established. While point mutations and seeds trigger the protein to cross the energy barriers, thus causing genetic and infectious transmissible spongiform encephalopathies, respectively, the mechanism responsible for sporadic forms remains unclear. Since prion diseases are protein-misfolding disorders, we investigated prion protein folding and stability as functions of different milieus. Using spectroscopic techniques and atomistic simulations, we dissected the contribution of major structural determinants, also defining the energy landscape of prion protein. In particular, we elucidated (i) the essential role of the octapeptide region in prion protein folding and stability, (ii) the presence of a very enthalpically stable intermediate in prion-susceptible species, and (iii) the role of the disulfide bridge in prion protein folding.
AB - Prions are responsible for a heterogeneous group of fatal neurodegenerative diseases, involving post-translational modifications of the cellular prion protein. Epidemiological studies on Creutzfeldt-Jakob disease, a prototype prion disorder, show a majority of cases being sporadic, while the remaining occurrences are either genetic or iatrogenic. The molecular mechanisms by which PrPC is converted into its pathological isoform have not yet been established. While point mutations and seeds trigger the protein to cross the energy barriers, thus causing genetic and infectious transmissible spongiform encephalopathies, respectively, the mechanism responsible for sporadic forms remains unclear. Since prion diseases are protein-misfolding disorders, we investigated prion protein folding and stability as functions of different milieus. Using spectroscopic techniques and atomistic simulations, we dissected the contribution of major structural determinants, also defining the energy landscape of prion protein. In particular, we elucidated (i) the essential role of the octapeptide region in prion protein folding and stability, (ii) the presence of a very enthalpically stable intermediate in prion-susceptible species, and (iii) the role of the disulfide bridge in prion protein folding.
KW - N-terminal domain
KW - disulfide bond
KW - energy landscape
KW - intermediate state
KW - prion-susceptible species
UR - http://www.scopus.com/inward/record.url?scp=84908192029&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000344205900010&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1016/j.jmb.2014.09.017
DO - 10.1016/j.jmb.2014.09.017
M3 - Article
C2 - 25280897
AN - SCOPUS:84908192029
SN - 0022-2836
VL - 426
SP - 3796
EP - 3810
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 22
ER -