Ser170 controls the conformational multiplicity of the loop 166-175 in prion proteins: Implication for conversion and species barrier

TitleSer170 controls the conformational multiplicity of the loop 166-175 in prion proteins: Implication for conversion and species barrier
Publication TypeJournal Article
Year of Publication2007
AuthorsGorfe A.A, Caflisch A.
JournalFASEB J
Volume21
Issue12
Pagination3279-3287
Date Published2007 Oct
Type of ArticleResearch Article
ISSN1530-6860
KeywordsAmino Acid Sequence, Animals, Cattle, Deer, Humans, Hydrogen Bonding, Mice, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Prion Diseases, Prions, Protein Structure, Secondary, Protein Structure, Tertiary, Recombinant Fusion Proteins, Serine, Solvents, Species Specificity
Abstract

The self-perpetuating conversion of cellular prion proteins (PrPC) into an aggregated β-sheet rich conformation is associated with transmissible spongiform encephalopathies (TSE). The loop 166-175 (L1) in PrPC, which displays sequence and structural variation among species, has been suggested to play a role in species barrier, in particular against transmission of TSE from cervids to domestic and laboratory animals. L1 is ordered in elk PrP, as well as in a mouse/elk hybrid (in which L1 of mouse is replaced by elk) but not in other species such as mice, humans, and bovine. To investigate the source and significance of L1 dynamics, we carried out explicit solvent molecular dynamics simulations (≈ 0.5 μs in total) of the mouse prion protein, the mouse/elk hybrid, and control simulations, in which the mouse sequence is reintroduced into the structure of the mouse/elk hybrid. We found that the flexibility of L1 correlates with the backbone dynamics of Ser170. Furthermore, L1 mobility promotes a substantial displacement of Tyr169, rupture of the Asp178-Tyr128 and Asp178-Tyr169 side chain hydrogen bonds, as well as disruption of Tyr169-Phe175 π-stacking interaction. The simulation results go beyond the available experimental data because they highlight the dependence of this network of interactions on residue 170 and L1 plasticity.

DOI10.1096/fj.07-8292com
pubindex

0088

Alternate JournalFASEB J.
PubMed ID17522379
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