Interplay of buried histidine protonation and protein stability in prion misfolding

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 me...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Anatoly Malevanets, P. Andrew Chong, D. Flemming Hansen, Paul Rizk, Yulong Sun, Hong Lin, Ranjith Muhandiram, Avi Chakrabartty, Lewis E. Kay, Julie D. Forman-Kay, Shoshana J. Wodak
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2cc9aa29f07a4e49a4b2965ad45484b5
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2cc9aa29f07a4e49a4b2965ad45484b5
record_format	dspace
spelling	oai:doaj.org-article:2cc9aa29f07a4e49a4b2965ad45484b52021-12-02T12:32:31ZInterplay of buried histidine protonation and protein stability in prion misfolding10.1038/s41598-017-00954-72045-2322https://doaj.org/article/2cc9aa29f07a4e49a4b2965ad45484b52017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00954-7https://doaj.org/toc/2045-2322Abstract 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.Anatoly MalevanetsP. Andrew ChongD. Flemming HansenPaul RizkYulong SunHong LinRanjith MuhandiramAvi ChakrabarttyLewis E. KayJulie D. Forman-KayShoshana J. WodakNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anatoly Malevanets P. Andrew Chong D. Flemming Hansen Paul Rizk Yulong Sun Hong Lin Ranjith Muhandiram Avi Chakrabartty Lewis E. Kay Julie D. Forman-Kay Shoshana J. Wodak Interplay of buried histidine protonation and protein stability in prion misfolding
description	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.
format	article
author	Anatoly Malevanets P. Andrew Chong D. Flemming Hansen Paul Rizk Yulong Sun Hong Lin Ranjith Muhandiram Avi Chakrabartty Lewis E. Kay Julie D. Forman-Kay Shoshana J. Wodak
author_facet	Anatoly Malevanets P. Andrew Chong D. Flemming Hansen Paul Rizk Yulong Sun Hong Lin Ranjith Muhandiram Avi Chakrabartty Lewis E. Kay Julie D. Forman-Kay Shoshana J. Wodak
author_sort	Anatoly Malevanets
title	Interplay of buried histidine protonation and protein stability in prion misfolding
title_short	Interplay of buried histidine protonation and protein stability in prion misfolding
title_full	Interplay of buried histidine protonation and protein stability in prion misfolding
title_fullStr	Interplay of buried histidine protonation and protein stability in prion misfolding
title_full_unstemmed	Interplay of buried histidine protonation and protein stability in prion misfolding
title_sort	interplay of buried histidine protonation and protein stability in prion misfolding
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2cc9aa29f07a4e49a4b2965ad45484b5
work_keys_str_mv	AT anatolymalevanets interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT pandrewchong interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT dflemminghansen interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT paulrizk interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT yulongsun interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT honglin interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT ranjithmuhandiram interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT avichakrabartty interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT lewisekay interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT juliedformankay interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding AT shoshanajwodak interplayofburiedhistidineprotonationandproteinstabilityinprionmisfolding
_version_	1718394027958599680

Interplay of buried histidine protonation and protein stability in prion misfolding

Ejemplares similares