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. 2021 Dec;15(1):155-176.
doi: 10.1080/19336896.2021.1964326.

Epitope-specific anti-PrP antibody toxicity: a comparative in-silico study of human and mouse prion proteins

Utpal Kumar Adhikari  1 , Mourad Tayebi  1
Affiliations

Epitope-specific anti-PrP antibody toxicity: a comparative in-silico study of human and mouse prion proteins

Utpal Kumar Adhikari et al. Prion. 2021 Dec.

Abstract

Despite having therapeutic potential, anti-PrP antibodies caused a major controversy due to their neurotoxic effects. For instance, treating mice with ICSM antibodies delayed prion disease onset, but both were found to be either toxic or innocuous to neurons by researchers following cross-linking PrPC. In order to elucidate and understand the reasons that led to these contradictory outcomes, we conducted a comprehensive in silico study to assess the antibody-specific toxicity. Since most therapeutic anti-PrP antibodies were generated against human truncated recombinant PrP91-231 or full-length mouse PrP23-231, we reasoned that host specificity (human vs murine) of PrPC might influence the nature of the specific epitopes recognized by these antibodies at the structural level possibly explaining the 'toxicity' discrepancies reported previously. Initially, molecular dynamics simulation and pro-motif analysis of full-length human (hu)PrP and mouse (mo)PrP 3D structure displayed conspicuous structural differences between huPrP and moPrP. We identified 10 huPrP and 6 moPrP linear B-cell epitopes from the prion protein 3D structure where 5 out of 10 huPrP and 3 out of 6 moPrP B-cell epitopes were predicted to be potentially toxic in immunoinformatics approaches. Herein, we demonstrate that some of the predicted potentially 'toxic' epitopes identified by the in silico analysis were similar to the epitopes recognized by the toxic antibodies such as ICSM18 (146-159), POM1 (138-147), D18 (133-157), ICSM35 (91-110), D13 (95-103) and POM3 (95-100). This in silico study reveals the role of host specificity of PrPC in epitope-specific anti-PrP antibody toxicity.

Keywords: B-cell epitope; Cellular prion protein (PrPc); immunoinformatics; molecular dynamics simulation; neurotoxicity.

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Conflict of interest statement

The author(s) declare no competing interests.

Figures

Figure 1.
Figure 1.
Multiple sequence alignment (MSA) between the huPrP and moPrP
Figure 2.
Figure 2.
Three-dimensional (3D) structure and topology of the huPrP and moPrP predicted by I-TASSER server
Figure 3.
Figure 3.
Evaluation of the 3D structure of the huPrP and moPrP
Figure 4.
Figure 4.
300 nanosecond (ns) molecular dynamics simulation (MDS) of the huPrP and moPrP
Figure 5.
Figure 5.
Analysis of the predicted linear and conformational B-cell epitopes and their position on the huPrP 3D structure
Figure 6.
Figure 6.
Analysis of the predicted linear and conformational B-cell epitopes and their position on the moPrP 3D structure
Figure 7.
Figure 7.
Potential toxicity analysis of the linear B-cell epitopes of both huPrP and moPrP protein
Figure 8.
Figure 8.
Properties of the potentially toxic linear B-cell epitope L2 (WGQGGGTHSQWNKPSKPKTNMKH) and L4 (PIIHFGSDYEDRYYREN) from the human major prion protein
Figure 9.
Figure 9.
Properties of the non-toxic linear B cell epitope L1 (GGSWGQPHGGGWGQGGGTHNQWNKPSKPKTNLKHVAGAAAAGAVVGG) and potentially toxic linear B-cell epitope L3 (PMIHFGNDWEDRYYRENMYRY) from the moPrP
Figure 10.
Figure 10.
Model of anti-PrP antibody-mediated toxicity prediction
See this image and copyright information in PMC

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