title: Structure of the β2-α2 loop and interspecies prion transmission.
abstract: Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The β2-α2 loop region of endogenous prion protein, PrP(C), has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar β2-α2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the β2-α2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered β2-α2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrP(C) from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Bett
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández-Borges
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Kurt
authors.forename: Melanie
authors.initials: M
authors.lastname: Lucero
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D002417:Cattle; D006224:Cricetinae; D003670:Deer; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018621:PrPC Proteins / Q000737:chemistry* / Q000235:genetics; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000635:transmission*; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D012756:Sheep; D013045:Species Specificity
chemical_list: D018621:PrPC Proteins; D011994:Recombinant Proteins