2mv9 | pdb_00002mv9
Solution structure of Ovis Aries PrP with mutation delta193-196
Structural highlights
DiseasePRIO_SHEEP Note=Polymorphism at position 171 may be related to the alleles of scrapie incubation-control (SIC) gene in this species. Note=Found in high quantity in the brain of humans and animals infected with degenerative neurological diseases such as kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler syndrome (GSS), scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), etc. Note=Scrapie is a transmissible neurodegenerative disorder of sheep and goats. Most sheep that contract the disease naturally die between 24 and 50 months of age. The incubation period in sheep depends on the strain(s) of the infecting pathogen, sheep age at exposure, and the sheep genotype. The survival time is mainly determined by a single genetic locus, SIP, which has two alleles, susceptible (sa) and resistant (pa). Short incubation period is conferred by the partially dominant sa allele. Scrapie can be spread between flockmates, or it can be transmitted from an infected ewe to its lamb. FunctionPRIO_SHEEP May play a role in neuronal development and synaptic plasticity. May be required for neuronal myelin sheath maintenance. May play a role in iron uptake and iron homeostasis. Soluble oligomers are toxic to cultured neuroblastoma cells and induce apoptosis (in vitro). Association with GPC1 (via its heparan sulfate chains) targets PRNP to lipid rafts. Also provides Cu(2+) or ZN(2+) for the ascorbate-mediated GPC1 deaminase degradation of its heparan sulfate side chains (By similarity). Publication Abstract from PubMedMammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha helical content, loosing the three alpha helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C-terminus of ovine PrP, as this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP expressing cells. Even more, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions. IMPORTANCE: Prions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date resolution of prion structure remains elusive. Thus to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C-terminus of alpha-helix H2, did not hamper prion formation, but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion. Generating bona fide mammalian prions with internal deletions.,Munoz-Montesino C, Sizun C, Moudjou M, Herzog L, Reine F, Chapuis J, Ciric D, Igel-Egalon A, Laude H, Beringue V, Rezaei H, Dron M J Virol. 2016 May 25. pii: JVI.00555-16. PMID:27226369[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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