Structural characterization of POM6 Fab and mouse prion protein complex identifies key regions for prions conformational conversion

Abstract

The structural data of moPrP:POM6 Fab complex are available in the PDB under the accession number www.rcsb.org/pdb/search/structidSearch.do?structureId=6AQ7.

Transition of the prion protein from a structured cellular form (PrPC) to the infectious scrapie agent (PrPSc)

“…So, many of the mammalian prion protein crystal structures have been determined by making complexes of the prion proteins with the Fab fragments of antiprion antibodies such as VRQ14, ICSM18, POM1, and POM6. 45,46 Structural comparisons of POM1 Fab: moPrP and POM6 Fab: moPrP complexes reveal subtle structural changes in the folded domain that could lead to the toxic misfolding process. Surprisingly, many of the C-terminal specific antibodies exhibited highly toxic behavior in biological experiments.…”

“…30,[44][45][46] These anti-prion monoclonal antibodies were being developed to act as therapeutic agents against the prion diseases by stabilizing the structured domain of the prion protein. 46 Several differences in hydrogen bonding interactions among residues from the β2-α2 loop and Y128 from strand-β1 have been observed along with the differences in the hydrophobic residue packing between helix α3 and the loop joining strand β1 and helix α1. 47 POM1 was found to be a highly toxic antibody that recognizes noncontiguous prion epitopes; the N-terminal part of helix α1, the loop structure joining strand β1 and helix α1, and few residues from helix α3.…”

“…So, many of the mammalian prion protein crystal structures have been determined by making complexes of the prion proteins with the Fab fragments of antiprion antibodies such as VRQ14, ICSM18, POM1, and POM6. 30,[44][45][46] These anti-prion monoclonal antibodies were being developed to act as therapeutic agents against the prion diseases by stabilizing the structured domain of the prion protein. Surprisingly, many of the C-terminal specific antibodies exhibited highly toxic behavior in biological experiments.…”

“…30 The binding epitopes of an innocuous antibody POM6 and the purportedly therapeutic antibody ICSM18 are nonoverlapping but adjacent to the prion epitope recognized by POM1 Fab. 45,46 Structural comparisons of POM1 Fab: moPrP and POM6 Fab: moPrP complexes reveal subtle structural changes in the folded domain that could lead to the toxic misfolding process. 46 Several differences in hydrogen bonding interactions among residues from the β2-α2 loop and Y128 from strand-β1 have been observed along with the differences in the hydrophobic residue packing between helix α3 and the loop joining strand β1 and helix α1.…”

“…45,46 Structural comparisons of POM1 Fab: moPrP and POM6 Fab: moPrP complexes reveal subtle structural changes in the folded domain that could lead to the toxic misfolding process. 46 Several differences in hydrogen bonding interactions among residues from the β2-α2 loop and Y128 from strand-β1 have been observed along with the differences in the hydrophobic residue packing between helix α3 and the loop joining strand β1 and helix α1. The Nterminal region-specific antibodies have been found to be therapeutic and prevent the scrapie challenge in POSCA (prion organotypic slice culture assay).…”