X-ray structural and molecular dynamical studies of the globular domains of cow, deer, elk and Syrian hamster prion proteins

Baral, Pravas Kumar; Swayampakula, Mridula; Aguzzi, Adriano; James, Michael N.G.

doi:10.1016/j.jsb.2015.08.014

Cited by 21 publications

(20 citation statements)

References 70 publications

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“…The blue and red graphs represent wt and the 116G polymorphism, respectively. The location of known secondary structure elements are shown using yellow and blue bars (top), on the crystal structure of deer prion protein (PDB ID: 4yxh [ 66 ]. ( g ) Solvent accessible surface area for both 116G PrP and wt PrP.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 201 templates were produced by the homology modelling search. Out of these, the crystal structure of deer prion protein (PDB: 4YXH [ 66 ]) model 1, chain A was chosen as the best template with a sequence identity of 99.01%, GMQE (Global Model Quality Estimation) score of 0.78 and a QMEAN4 score of -0.10. Finally, the SWISS-MODEL homology modelling server was used to build the 3D model [ 65 ].…”

Section: Methodsmentioning

confidence: 99%

“…The complete construct 112–233 of wild type WTD prion generated by Accelrys VS [ 67 ] and equilibrated with MD was used as the control model. Finally, using the SWISS-MODEL homology modelling server, the model for the 116G polymorphism was generated based on the PDB file of the wt PrP structure (PDB: 4YXH [ 66 ]).…”

Section: Methodsmentioning

confidence: 99%

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Destabilizing polymorphism in cervid prion protein hydrophobic core determines prion conformation and conversion efficiency

et al. 2017

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Prion diseases are infectious neurodegenerative disorders of humans and animals caused by misfolded forms of the cellular prion protein PrPC. Prions cause disease by converting PrPC into aggregation-prone PrPSc. Chronic wasting disease (CWD) is the most contagious prion disease with substantial lateral transmission, affecting free-ranging and farmed cervids. Although the PrP primary structure is highly conserved among cervids, the disease phenotype can be modulated by species-specific polymorphisms in the prion protein gene. How the resulting amino-acid substitutions impact PrPC and PrPSc structure and propagation is poorly understood. We investigated the effects of the cervid 116A>G substitution, located in the most conserved PrP domain, on PrPC structure and conversion and on 116AG-prion conformation and infectivity. Molecular dynamics simulations revealed structural de-stabilization of 116G-PrP, which enhanced its in vitro conversion efficiency when used as recombinant PrP substrate in real-time quaking-induced conversion (RT-QuIC). We demonstrate that 116AG-prions are conformationally less stable, show lower activity as a seed in RT-QuIC and exhibit reduced infectivity in vitro and in vivo. Infectivity of 116AG-prions was significantly enhanced upon secondary passage in mice, yet conformational features were retained. These findings indicate that structurally de-stabilized PrPC is readily convertible by cervid prions of different genetic background and results in a prion conformation adaptable to cervid wild-type PrP. Conformation is an important criterion when assessing transmission barrier, and conformational variants can target a different host range. Therefore, a thorough analysis of CWD isolates and re-assessment of species-barriers is important in order to fully exclude a zoonotic potential of CWD.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Destabilizing polymorphism in cervid prion protein hydrophobic core determines prion conformation and conversion efficiency

et al. 2017

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“…The monoclonal antibody ICSM18 recognizes huPrP(119–231) [63], VRQ14 Fab binds to ovine PrP C and to PrP Sc , [64] POM1 Fab binds PrP C from many species[65, 66], and nanobody Nb484 binds to full length human prion protein[67]. These antibodies recognize different epitopes, residues 143–156 for ICSM18, residues 140–147 and 204–212 for POM1, and 188–199 for VRQ14.…”

Section: Introductionmentioning

confidence: 99%

“…Molecular dynamics simulation studies on six prion proteins (cow, deer, elk, Syrian hamster, mouse and human) revealed differences in the local fluctuations and imply that these differences have possible roles in the unfolding of the globular domains and the strain selection and the preferred conformations adopted upon binding. [66]…”

Section: Introductionmentioning

confidence: 99%

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Zhao

Nussinov

2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background The dominant feature in neurodegenerative diseases is protein aggregations that lead to neuronal loss. Immunotherapies using antibodies or antibody fragments to target the aggregations are a highly perused approach. The molecular mechanisms underlying the amyloid-based immunotherapy are complex. Deciphering the properties of amyloidogenic proteins responsible for these diseases is essential to obtain insights into antibody recognition of the amyloid antigens. Scope of Review We systematically explore all available crystal structures of antibody-amyloid complexes related to neurodegenerative diseases, including antibodies that recognize the Aβ peptide, tau protein, prion protein, alpha-synuclein, huntingtin protein (mHTT), and polyglutamine. Major Conclusions We found that antibodies mostly use the conformational selection mechanism to recognize the highly flexible amyloid antigens. In particular, solanezumab bound to Aβ12–28 tripeptide motif conformation (F19F20A21), which is shared with the Aβ42 fibril. This motif, which is trapped by the antibody, may provide the missing link in amyloid formation. Water molecules often bridge between the antibody and amyloid, contributing to the recognition. General Significance This paper provides the structural basis for antibody recognition of amyloidogenic proteins. The analysis and discussion of known structures are expected to help in the design and optimization of antibodies in neurodegenerative diseases.

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Prion protein conversion triggered by acidic condition: a molecular dynamics study through different force fields

Thompson

Caceres

et al. 2018

J Comput Chem

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Prions are proteins that cause a group of invariably fatal neurodegenerative diseases, one of the most known being bovine spongiform encephalopathy. The three‐dimensional structure of PrPSc, the altered isoform of the prion protein, has not been fully elucidated yet, and studies on prion conversion mechanisms must rely on hypothetical β‐rich structures. Experimental and computational studies indicate that the use of low pH is capable to produce a gain of β‐structure content in the otherwise unstructured N‐terminal region. These in silico studies have used different PrP fragments from distinct organisms, and with different lengths and simulation protocols, making it difficult to identify the influence of the force fields on the formation of such structures. Here, we performed a systematic study of the influence of six well‐established force fields (GROMOS96 53a6, GROMOS96 43a1, AMBER99SB, AMBER99SB‐ILDN, CHARMM27, and OPLS‐AA/L) on the process of structural conversion of the Syrian hamster cellular prion protein simulated at acidic and neutral pH. From our analysis, we observe a strong dependence of the results with the different force fields employed. Additionally, only GROMOS96 53A6 and AMBER99SB force fields are capable to capture a high β‐sheet formation at acidic pH and adequately reproduce the neutral pH. In both cases, the β‐sheet elongation seems to be guided by the movement of the N‐terminal tail toward the N‐terminal of α‐helix HB under acidic condition. These results comprise the most wide‐ranging study to date correlating force fields to structural changes in the cellular prion protein. © 2018 Wiley Periodicals, Inc.

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X-ray structural and molecular dynamical studies of the globular domains of cow, deer, elk and Syrian hamster prion proteins

Cited by 21 publications

References 70 publications

Destabilizing polymorphism in cervid prion protein hydrophobic core determines prion conformation and conversion efficiency

Destabilizing polymorphism in cervid prion protein hydrophobic core determines prion conformation and conversion efficiency

Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes

Prion protein conversion triggered by acidic condition: a molecular dynamics study through different force fields

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