Conformational diversity in prion protein variants influences intermolecular β-sheet formation

Abstract

A conformational transition of normal cellular prion protein (PrP C ) to its pathogenic form (PrP Sc ) is believed to be a central event in the transmission of the devastating neurological diseases known as spongiform encephalopathies. The common methionine/valine polymorphism at residue 129 in the PrP influences disease susceptibility and phenotype. We report here seven crystal structures of human PrP variants: three of wild-type (WT) PrP containing V129, and four of the familial variants D178N and F198S, containing either M129 or V129. Comparison of these structures with each other and with previously published WT PrP structures containing M129 revealed that only WT PrPs were found to crystallize as domainswapped dimers or closed monomers; the four mutant PrPs crystallized as non-swapped dimers. Three of the four mutant PrPs aligned to form intermolecular b-sheets. Several regions of structural variability were identified, and analysis of their conformations provides an explanation for the structural features, which can influence the formation and conformation of intermolecular b-sheets involving the M/V129 polymorphic residue.

Molecular Dynamics as an Approach to Study Prion Protein Misfolding and the Effect of Pathogenic Mutations

“…Spin-labeling ESR studies of D178N PrP indeed showed that the D178N mutation increases instability in S2 [139]. Crystal structures of D178N PrP with either M129 or V129 show little difference with the overall static fold of WT PrP [75]. Differential packing of the monomers, however, indicates that the native β-sheet may combine to form an intermolecular 4-stranded sheet with M129, but not with V129.…”

“…For PrP, the first [8] and most abundant structural information has been obtained by nuclear magnetic resonance techniques (NMR), which has resulted in experimentally derived models of PrP of a wide variety of species [64][65][66][67][68][69][70]. For human and sheep PrP, structures determined by X-ray crystallography have also been reported, both with and without antibodies bound [71][72][73][74][75]. The overall structure of PrP that has emerged from these studies is largely identical for the different species and conditions.…”

“…MD simulations can be used to study the effect of these mutations on protein conformation and stability, particularly for the 24 mutations that are found in the C-terminal folded domain of human PrP [124][125][126]. Structural biology can also offer insights into the structural effect of pathogenic mutations [75,127] (see also chapter Y by Surewicz et al). In some cases, however, structural studies do not reveal differences between wild-type and mutant proteins whereas MD simulations do (see e.g.…”

A review on the salt bridge ASP177-ARG163 (O–N) of wild-type rabbit prion protein

“…We have found one focus of prion protein structures is at the β2-α2 loop and its interacted Cterminal of H3 (Biljan et al, 2012a(Biljan et al, & 2012b(Biljan et al, & 2011Calzolai et al, 2000;Christen et al, 2009Christen et al, & 2012Damberger et al, 2011;Gossert et al, 2005;Ilc et al, 2010;Lee et al, 2010;Wen et al, 2010aWen et al, & 2010bKong et al, 2013;Perez et al, 2010Perez et al, & 2008Sweeting et al, 2013;Zahn et al, 2003;Zhang et al, 2000;Kurt et al, 2014aKurt et al, & 2014b. This article found there is a SB ASP177-ARG163 (O-N) in RaPrP C , which just keeps this loop being linked.…”

Mechanisms of Cell Death in the Transmissible Spongiform Encephalopathies

“…The atomic level structures of such isoforms have been defined by both nuclear magnetic resonance (NMR) spectroscopy, for a range of different prion proteins e.g. , Christen et al, 2008, Gossert et al, 2005, Perez et al, 2010, Wuthrich & Riek, 2001, and X-ray crystallography for sheep (Eghiaian et al, 2004, Haire et al, 2004 human (Antonyuk et al, 2009, Knaus et al, 2001, Lee et al, 2010 and rabbit proteins (Khan et al, 2010). These studies found that the Cterminal region of PrP has globular structure (depicted in Fig 3) and NMR investigations of native PrP C purified from cattle brains confirmed these structural assignments (Hornemann et al, 2004).…”