Prion disease susceptibility is affected by β-structure folding propensity and local side-chain interactions in PrP

Khan, Mashiat; Sweeting, Braden; Mulligan, Vikram Khipple; Arslan, Pharhad Eli; Cashman, Neil R.; Pai, E.F.; Chakrabartty, Avijit

doi:10.1073/pnas.1005267107

Cited by 123 publications

(162 citation statements)

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“…Recently, some researchers (6,47,48,49,50,51,52) reported that the β2-α2 loop plays an important role to stabilize the structural stability of rabbit and horse prion proteins. This conclusion can be confirmed from the hydrogen bond, hydrophobic bond, and salt bridge databases on horse prion protein presented by this paper.…”

Section: Resultsmentioning

confidence: 99%

The Structural Stability of Wild-type Horse Prion Protein

Zhang

2011

Journal of Biomolecular Structure and Dynamics

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Prion diseases (e.g. Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), GerstmannSträussler-Scheinker syndrome (GSS), Fatal Familial Insomnia (FFI) and Kuru in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE or 'mad-cow' disease) and chronic wasting disease (CWD) in cattles) are invariably fatal and highly infectious neurodegenerative diseases affecting humans and animals. However, by now there have not been some effective therapeutic approaches or medications to treat all these prion diseases. Rabbits, dogs, and horses are the only mammalian species reported to be resistant to infection from prion diseases isolated from other species. Recently, the β2-α2 loop has been reported to contribute to their protein structural stabilities. The author has found that rabbit prion protein has a strong salt bridge ASP177-ARG163 (like a taut bow string) keeping this loop linked. This paper confirms that this salt bridge also contributes to the structural stability of horse prion protein. Thus, the region of β2-α2 loop might be a potential drug target region. Besides this very important salt bridge, other four important salt bridges GLU196-ARG156-HIS187, ARG156-ASP202 and GLU211-HIS177 are also found to greatly contribute to the structural stability of horse prion protein. Rich databases of salt bridges, hydrogen bonds and hydrophobic contacts for horse prion protein can be found in this paper.

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Section: Resultsmentioning

confidence: 99%

The Structural Stability of Wild-type Horse Prion Protein

Zhang

2011

Journal of Biomolecular Structure and Dynamics

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“…Although β2-α2 loop rigidity was thought to potentiate PrP C to PrP Sc conversion (24), subsequent studies revealed that PrP C of species considered resistant to prions, including horses, also contained rigid β2-α2 loops (25)(26)(27). Adding additional complexity, Tg mice expressing mouse PrP C containing rigid β2-α2 loops from elk or horse PrP spontaneously developed prion diseases (28,29).…”

Section: Significancementioning

confidence: 99%

Prion replication without host adaptation during interspecies transmissions

Bian

Khaychuk

Angers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPCalso failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.

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“…This screen revealed a feature in the elk prion protein, where all backbone amide group NMR signals of the β2−α2 loop are observable at 20°C and a 1 H resonance frequency of 750 MHz; the β2−α2 loop is, therefore, well-defined in the NMR structure (23). This observation attracted special interest in the context of the CWD crisis of deer and elk in North America (34-37) and was followed up by structural studies of WT and specifically designed variant prion proteins (24-26, 28, 38), in vivo experiments with transgenic mice (11,13,14,39,40), and in vitro studies of correlations between the β2-α2 loop amino acid sequence and the propensity of PrP C to undergo transitions to PrP Sc -related conformations (41)(42)(43). In connection with animal experiments relating to CWD, the term RL-PrP C was introduced for PrP C s forming a structurally well-defined β2−α2 loop in the solution NMR structure at 20°C (39).…”

Section: T Ransmissible Spongiform Encephalopathies (Tses) Includementioning

confidence: 99%

Structural plasticity of the cellular prion protein and implications in health and disease

Christen¹,

Damberger²,

Pérez³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Two lines of transgenic mice expressing mouse/elk and mouse/ horse prion protein (PrP) hybrids, which both form a well-structured β2-α2 loop in the NMR structures at 20°C termed rigid-loop cellular prion proteins (RL-PrP C ), presented with accumulation of the aggregated scrapie form of PrP in brain tissue, and the mouse/ elk hybrid has also been shown to develop a spontaneous transmissible spongiform encephalopathy. Independently, there is in vitro evidence for correlations between the amino acid sequence in the β2-α2 loop and the propensity for conformational transitions to disease-related forms of PrP. To further contribute to the structural basis for these observations, this paper presents a detailed characterization of RL-PrP C conformations in solution. A dynamic local conformational polymorphism involving the β2-α2 loop was found to be evolutionarily preserved among all mammalian species, including those species for which the WT PrP forms an RL-PrP C . The interconversion between two ensembles of PrP C conformers that contain, respectively, a 3 10 -helix turn or a type I β-turn structure of the β2-α2 loop, exposes two different surface epitopes, which are analyzed for their possible roles in the still evasive function of PrP C in healthy organisms and/or at the onset of a transmissible spongiform encephalopathy. Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, bovine spongiform encephalopathy in cattle, and chronic wasting disease (CWD) in elk and deer (1-3). A common feature of these diseases is the conversion of the cellular form of the prion protein (PrP C ) found in healthy organisms into aggregated isoforms (PrP Sc ), which are deposited primarily in the brain of the diseased individuals (1, 4). Despite extensive investigations, the physiological function of PrP C in healthy organisms as well as the mechanistic aspects of its pathophysiological role remain elusive (4-9). Although the PrP Sc form found in diseased tissue has been intensively studied, other approaches underline the importance of PrP C as a potential target for TSE prevention and medical intervention after outbreak of the disease (10-12), with a special focus on rigid-loop cellular prion proteins (RL-PrP C s) (11,(13)(14)(15), which are investigated in this paper.A common PrP C fold for a globular domain formed by the polypeptide segment of residues 125-228 in mouse PrP (mPrP) [see Schätzl et al. (16) for the numeration in different species], with three α-helices and a short two-stranded antiparallel β-sheet, has been observed for the cellular prion proteins of all mammalian species studied so far (17-27). For WT PrP of most species, parts of the backbone amide group NMR signals of residues in a loop between a β-strand, β2, and a helix, α2, are not observable in NMR spectra recorded with aqueous solutions at pH 4.5 and 20°C at a 1 H resonance frequency of 500 MHz (or higher) because of line broadening by conformational exchange; therefore, the β2-α2 loop in these PrP C s is poorly defined in NMR structures determined un...

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Prion disease susceptibility is affected by β-structure folding propensity and local side-chain interactions in PrP

Cited by 123 publications

References 45 publications

The Structural Stability of Wild-type Horse Prion Protein

The Structural Stability of Wild-type Horse Prion Protein

Prion replication without host adaptation during interspecies transmissions

Structural plasticity of the cellular prion protein and implications in health and disease

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