Structure of infectious prions: stabilization by domain swapping.
A candidate structure for the minimal prion infectious unit is a recently discovered protein oligomer modeled as a beta-helical prion trimer (BPT); BPTs can stack to form cross-beta fibrils and may provide insight into protein aggregates of other amyloid diseases. However, the BPT lacks a clear intermonomer binding mechanism. Here we propose an alternative domain-swapped trimeric prion (DSTP) model and show with molecular dynamics (MD) that the DSTP has more favorable intermonomer hydrogen bonding and proline dihedral strain energy than the BPT. This new structural proposal may be tested by lysine and N terminus fluorescent resonance energy transfer (FRET) either directly on recombinant prion protein amyloid aggregates or on synthetic constructs that contain the proline/lysine-rich hinge region critical for domains to swap. In addition, the domain swapping may provide 1) intrinsic entanglement, which can contribute to the remarkable temperature stability of the infectious prion structure and help explain the absence of PrP(Sc) monomers, 2) insight into why specific prolines are potentially relevant to three inherited forms of prion disease, and 3) a simple explanation of prion strains assuming the strain is encoded in the monomer number of the oligomers.
Yang
Sichun
S
Center for Theoretical Biological Physics, University of California San Diego, La Jolla, California 92093-0374, USA.
Levine
Herbert
H
Onuchic
José N
JN
Cox
Daniel L
DL
D000682:Amyloid / Q000737:chemistry; D000818:Animals; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D006860:Hydrogen Bonding; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008962:Models, Theoretical; D018620:PrPSc Proteins / Q000737:chemistry*; D011328:Prions / Q000737:chemistry*; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D012984:Software; D013696:Temperature
D000682:Amyloid; D018620:PrPSc Proteins; D011328:Prions; D011994:Recombinant Proteins; D011392:Proline; D008239:Lysine