Dual Conformation of H2H3 Domain of Prion Protein in Mammalian Cells

Xu, Zhou; Prigent, Stéphanie; Deslys, Jean‐Philippe; Rézaei, Human

doi:10.1074/jbc.m111.275255

Cited by 14 publications

(24 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, our previous study of the misfolding propensity of mPrP using extensive REMD simulations [16] has revealed that various monomers can be formed from the C-terminal domain alone, which is also consistent with the results of Ref. [5], [6].…”

Section: Introductionsupporting

confidence: 86%

“…According to the so-called “spiral” [2] and “” [3], [4] models, extended are formed in the N-terminal region and at the beginning of the C-terminal domain up to H1 (H1 is kept intact in the former and is refolded in the latter model). However, it has been recently shown that the H2H3 core is also highly fibrillogenic by itself [5], [6]. Finally, it has also been suggested that could be entirely refolded in an in-register extended [7].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Two Misfolding Routes for the Prion Protein around pH 4.5

2013

View full text Add to dashboard Cite

Using molecular dynamics simulations, we show that the prion protein (PrP) exhibits a dual behavior, with two possible transition routes, upon protonation of H187 around pH 4.5, which mimics specific conditions encountered in endosomes. Our results suggest a picture in which the protonated imidazole ring of H187 experiences an electrostatic repulsion with the nearby guanidinium group of R136, to which the system responds by pushing either H187 or R136 sidechains away from their native cavities. The regions to which H187 and R136 are linked, namely the C-terminal part of H2 and the loop connecting S1 to H1, respectively, are affected in a different manner depending on which pathway is taken. Specific in vivo or in vitro conditions, such as the presence of molecular chaperones or a particular experimental setup, may favor one transition pathway over the other, which can result in very different monomers. This has some possible connections with the observation of various fibril morphologies and the outcome of prion strains. In addition, the finding that the interaction of H187 with R136 is a weak point in mammalian PrP is supported by the absence of the residue pair in non-mammalian species that are known to be resistant to prion diseases.

show abstract

Section: Introductionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Two Misfolding Routes for the Prion Protein around pH 4.5

2013

View full text Add to dashboard Cite

show abstract

“…In summary, it was evident that a substantial part of N-glycans of Δ31–160 and variants of it were EndoH-resistant. This fraction of PrP might exit ER, pass medial Golgi and reach endosomal/lysosomal compartments [47] or the cell surface, being consistent with the cell-surface distribution of a mutant PrP with the similar structure [50].…”

Section: Resultssupporting

confidence: 78%

Critical Significance of the Region between Helix 1 and 2 for Efficient Dominant-Negative Inhibition by Conversion-Incompetent Prion Protein

et al. 2013

View full text Add to dashboard Cite

Prion diseases are fatal infectious neurodegenerative disorders in man and animals associated with the accumulation of the pathogenic isoform PrPSc of the host-encoded prion protein (PrPc). A profound conformational change of PrPc underlies formation of PrPSc and prion propagation involves conversion of PrPc substrate by direct interaction with PrPSc template. Identifying the interfaces and modalities of inter-molecular interactions of PrPs will highly advance our understanding of prion propagation in particular and of prion-like mechanisms in general. To identify the region critical for inter-molecular interactions of PrP, we exploited here dominant-negative inhibition (DNI) effects of conversion-incompetent, internally-deleted PrP (ΔPrP) on co-expressed conversion-competent PrP. We created a series of ΔPrPs with different lengths of deletions in the region between first and second α-helix (H1∼H2) which was recently postulated to be of importance in prion species barrier and PrP fibril formation. As previously reported, ΔPrPs uniformly exhibited aberrant properties including detergent insolubility, limited protease digestion resistance, high-mannose type N-linked glycans, and intracellular localization. Although formerly controversial, we demonstrate here that ΔPrPs have a GPI anchor attached. Surprisingly, despite very similar biochemical and cell-biological properties, DNI efficiencies of ΔPrPs varied significantly, dependant on location and inversely correlated with the size of deletion. This data demonstrates that H1∼H2 and the region C-terminal to it are critically important for efficient DNI. It also suggests that this region is involved in PrP-PrP interaction and conversion of PrPC into PrPSc. To reconcile the paradox of how an intracellular PrP can exert DNI, we demonstrate that ΔPrPs are subject to both proteasomal and lysosomal/autophagic degradation pathways. Using autophagy pathways ΔPrPs obtain access to the locale of prion conversion and PrPSc recycling and can exert DNI there. This shows that the intracellular trafficking of PrPs is more complex than previously anticipated.

show abstract

“…4a Recently, the H2H3 region was shown to undergo glycosyl phospho-inositol anchoring in cells, similarly to the full length PrP, and to undergo a conversion process with the generation of insoluble PK-resistant aggregates. 8 …”

Section: Introductionmentioning

confidence: 99%

Decrypting Prion Protein Conversion into a β-Rich Conformer by Molecular Dynamics

Chakroun

Fornili

Prigent

et al. 2013

J. Chem. Theory Comput.

Self Cite

View full text Add to dashboard Cite

Prion diseases are fatal neurodegenerative diseases characterized by the formation of β-rich oligomers and the accumulation of amyloid fibrillar deposits in the central nervous system. Understanding the conversion of the cellular prion protein into its β-rich polymeric conformers is fundamental to tackling the early stages of the development of prion diseases. In this paper, we have identified unfolding and refolding steps critical to the conversion into a β-rich conformer for different constructs of the ovine prion protein by molecular dynamics simulations. By combining our results with in vitro experiments, we show that the folded C-terminus of the ovine prion protein is able to recurrently undergo a drastic conformational change by displacement of the H1 helix, uncovering of the H2H3 domain, and formation of persistent β-sheets between H2 and H3 residues. The observed β-sheets refold toward the C-terminus exposing what we call a “bending region” comprising residues 204–214. This is strikingly coincident with the region harboring mutations determining the fate of the prion oligomerization process. The β-rich intermediate is used here for the construction of a putative model for the assembly into an oligomeric aggregate. The results presented here confirm the importance of the H2H3 domain for prion oligomer formation and therefore its potential use as molecular target in the design of novel prion inhibitors.

show abstract

Dual Conformation of H2H3 Domain of Prion Protein in Mammalian Cells

Cited by 14 publications

References 42 publications

Two Misfolding Routes for the Prion Protein around pH 4.5

Two Misfolding Routes for the Prion Protein around pH 4.5

Critical Significance of the Region between Helix 1 and 2 for Efficient Dominant-Negative Inhibition by Conversion-Incompetent Prion Protein

Decrypting Prion Protein Conversion into a β-Rich Conformer by Molecular Dynamics

Contact Info

Product

Resources

About