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Structure of infectious prions: stabilization by domain swapping
Author(s) -
Yang Sichub,
Levine Herbert,
Onuchic José N.,
Cox Daniel L.
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4067hyp
Subject(s) - trimer , chemistry , förster resonance energy transfer , oligomer , monomer , protein folding , molecular dynamics , protein structure , biophysics , prion protein , dihedral angle , dimer , crystallography , hydrogen bond , fluorescence , biochemistry , biology , molecule , computational chemistry , medicine , physics , disease , organic chemistry , pathology , quantum mechanics , polymer
A candidate structure for the minimal prion infectious unit is a recently discovered protein oligomer modeled as a β‐helical prion trimer (BPT); BPTs can stack to form cross‐β 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, S., Levine, H., Onuchic, J. N., Cox, D. L. Structure of infectious prions: stabilization by domain swapping. FASEB J. 19, 1778–1782 (2005)