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Structural and Dynamic Properties of the Human Prion Protein

Prion diseases involve the conformational conversion of the cellular prion protein (PrP ) to its misfolded pathogenic form (PrP ). To better understand the structural mechanism of this conversion, we performed extensive all-atom, explicit-solvent molecular-dynamics simulations for three structures o... Full description

Journal Title: Biophysical Journal 04 March 2014, Vol.106(5), pp.1152-1163
Main Author: Chen, Wei
Other Authors: Van der kamp, Marc w , Daggett, Valerie
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0006-3495 ; E-ISSN: 1542-0086 ; DOI: 10.1016/j.bpj.2013.12.053
Link: https://www.sciencedirect.com/science/article/pii/S0006349514001325
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recordid: elsevier_sdoi_10_1016_j_bpj_2013_12_053
title: Structural and Dynamic Properties of the Human Prion Protein
format: Article
creator:
  • Chen, Wei
  • Van der kamp, Marc w
  • Daggett, Valerie
subjects:
  • Biology
ispartof: Biophysical Journal, 04 March 2014, Vol.106(5), pp.1152-1163
description: Prion diseases involve the conformational conversion of the cellular prion protein (PrP ) to its misfolded pathogenic form (PrP ). To better understand the structural mechanism of this conversion, we performed extensive all-atom, explicit-solvent molecular-dynamics simulations for three structures of the wild-type human PrP (huPrP) at different pH values and temperatures. Residue 129 is polymorphic, being either Met or Val. Two of the three structures have Met in position 129 and the other has Val. Lowering the pH or raising the temperature induced large conformational changes of the C-terminal globular domain and increased exposure of its hydrophobic core. In some simulations, HA and its preceding S1-HA loop underwent large displacements. The C-terminus of HB was unstable and sometimes partially unfolded. Two hydrophobic residues, Phe-198 and Met-134, frequently became exposed to solvent. These conformational changes became more dramatic at lower pH or higher temperature. Furthermore, Tyr-169 and the S2-HB loop, or the X-loop, were different in the starting structures but converged to common conformations in the simulations for the Met-129, but not the Val-129, protein. -Strands and -strands formed in the initially unstructured N-terminus. -Strand propensity in the N-terminus was different between the Met-129 and Val129 proteins, but -strand propensity was similar. This study reveals detailed structural and dynamic properties of huPrP, providing insight into the mechanism of the conversion of PrP to PrP .
language: eng
source:
identifier: ISSN: 0006-3495 ; E-ISSN: 1542-0086 ; DOI: 10.1016/j.bpj.2013.12.053
fulltext: fulltext
issn:
  • 0006-3495
  • 00063495
  • 1542-0086
  • 15420086
url: Link


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descriptionPrion diseases involve the conformational conversion of the cellular prion protein (PrP ) to its misfolded pathogenic form (PrP ). To better understand the structural mechanism of this conversion, we performed extensive all-atom, explicit-solvent molecular-dynamics simulations for three structures of the wild-type human PrP (huPrP) at different pH values and temperatures. Residue 129 is polymorphic, being either Met or Val. Two of the three structures have Met in position 129 and the other has Val. Lowering the pH or raising the temperature induced large conformational changes of the C-terminal globular domain and increased exposure of its hydrophobic core. In some simulations, HA and its preceding S1-HA loop underwent large displacements. The C-terminus of HB was unstable and sometimes partially unfolded. Two hydrophobic residues, Phe-198 and Met-134, frequently became exposed to solvent. These conformational changes became more dramatic at lower pH or higher temperature. Furthermore, Tyr-169 and the S2-HB loop, or the X-loop, were different in the starting structures but converged to common conformations in the simulations for the Met-129, but not the Val-129, protein. -Strands and -strands formed in the initially unstructured N-terminus. -Strand propensity in the N-terminus was different between the Met-129 and Val129 proteins, but -strand propensity was similar. This study reveals detailed structural and dynamic properties of huPrP, providing insight into the mechanism of the conversion of PrP to PrP .
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