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Prion Protein-Antibody Complexes Characterized by Chromatography-Coupled Small-Angle X-Ray Scattering
Lester Carter1, Seung Joong Kim2, Dina Schneidman-Duhovny2
1Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, California.
Biophysical Journal
|August 20, 2015
Summary
Antibodies targeting prion proteins (PrP) may prevent neurodegenerative diseases by blocking the misfolding of cellular PrP (PrP(C)) into disease-causing PrP(Sc) aggregates. Structural analysis of PrP-antibody complexes reveals potential therapeutic mechanisms.
Area of Science:
- Neuroscience
- Structural Biology
- Biochemistry
Background:
- Aberrant self-assembly of prion proteins, specifically the misfolding of cellular prion protein (PrP(C)) into a β-sheet-rich isoform (PrP(Sc)), underlies neurodegenerative disorders.
- The precise molecular mechanisms driving PrP(C)-to-PrP(Sc) conversion and subsequent aggregation are not fully understood.
- Previous studies demonstrated that monoclonal antibodies targeting specific prion protein regions can clear PrP(Sc) in cell culture.
Purpose of the Study:
- To investigate the structural characteristics of prion protein (PrP)-antibody complexes in solution.
- To elucidate the mechanisms by which antibodies might inhibit the conversion of PrP(C) to PrP(Sc).
Main Methods:
- Utilized fast protein liquid chromatography coupled with small-angle X-ray scattering (FPLC-SAXS) for in-line structural analysis.
- Collected high-quality SAXS data for full-length recombinant mouse PrP [recPrP(23-230)] and a truncated form [recPrP(89-230)].
- Analyzed complexes of PrP with two Fab fragments (HuM-P and HuM-R1) targeting distinct PrP epitopes.
Main Results:
- FPLC-SAXS minimized artifacts from non-monodispersed samples, enabling accurate structural analysis.
- Structural models were generated for PrP alone and in complex with Fab antibodies.
- The study identified two potential mechanisms through which Fabs may inhibit PrP(C) to PrP(Sc) conversion.
Conclusions:
- Antibody binding to specific prion protein epitopes can influence PrP structure.
- These structural insights provide a basis for understanding how antibodies might prevent prion-related neurodegeneration.
- Further research into PrP-antibody interactions could lead to novel therapeutic strategies for prion diseases.
