Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

The cellular prion protein (PrPC) comprises a natively unstructured N‐terminal domain, including a metal‐binding octarepeat region (OR) and a linker, followed by a C‐terminal domain that misfolds to form PrPSc in Creutzfeldt‐Jakob disease. PrPC β‐endoproteolysis to the C2 fragment allows PrPSc formation, while α‐endoproteolysis blocks production. To examine the OR, we used structure‐directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion‐infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal‐catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease.

• Publication year

  2015

• Venue

  EMBO Molecular Medicine

• Publication date

  2015-02-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.15252/emmm.201404588PMID 25661904PMCID 4364950
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice

  2017influential reference
• Prion disease tempo determined by host-dependent substrate reduction.

  2014cited by this paper
• A New Paradigm for Enzymatic Control of α-Cleavage and β-Cleavage of the Prion Protein*

  2013cited by this paper
• Zinc drives a tertiary fold in the prion protein with familial disease mutation sites at the interface.

  2013cited by this paper
• The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein

  2013cited by this paper
• Small Protease Sensitive Oligomers of PrPSc in Distinct Human Prions Determine Conversion Rate of PrPC

  2012cited by this paper
• Human prion protein binds Argonaute and promotes accumulation of microRNA effector complexes

  2012cited by this paper
• Prion propagation, toxicity and degradation

  2012cited by this paper
• The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes

  2012cited by this paper
• Copper Alters Aggregation Behavior of Prion Protein and Induces Novel Interactions between Its N- and C-terminal Regions

  2011cited by this paper
• Prion protein expression level alters regional copper, iron and zinc content in the mouse brain.

  2011cited by this paper
• Prion propagation and toxicity in vivo occur in two distinct mechanistic phases

  2011cited by this paper
• The prion protein unstructured N‐terminal region is a broad‐spectrum molecular sensor with diverse and contrasting potential functions

  2011cited by this paper
• A Naturally Occurring C-terminal Fragment of the Prion Protein (PrP) Delays Disease and Acts as a Dominant-negative Inhibitor of PrPSc Formation*

  2011cited by this paper
• Structure of the flexible amino-terminal domain of prion protein bound to a sulfated glycan.

  2010cited by this paper
• Protease-Sensitive Synthetic Prions

  2010cited by this paper
• Generating a Prion with Bacterially Expressed Recombinant Prion Protein

  2010cited by this paper
• Endogenous Proteolytic Cleavage of Disease-associated Prion Protein to Produce C2 Fragments Is Strongly Cell- and Tissue-dependent*

  2010cited by this paper
• Axonal prion protein is required for peripheral myelin maintenance

  2010influential reference
• Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers

  2009cited by this paper
• alpha-cleavage of the prion protein occurs in a late compartment of the secretory pathway and is independent of lipid rafts.

  2009cited by this paper
• A Potential Mechanism for Cu2+ Reduction, β-Cleavage, and β-Sheet Initiation Within The N-Terminal Domain of the Prion Protein: Insights from Density Functional Theory and Molecular Dynamics Calculations

  2009cited by this paper
• Increased Proportions of C1 Truncated Prion Protein Protect Against Cellular M1000 Prion Infection

  2009cited by this paper
• Faculty Opinions recommendation of Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.

  2009cited by this paper
• Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt-Jakob disease

  2009cited by this paper
• Transmissible spongiform encephalopathy strain-associated diversity of N-terminal proteinase K cleavage sites of PrPSc from scrapie-infected and bovine spongiform encephalopathy-infected mice

  2008cited by this paper
• Modeling by assembly and molecular dynamics simulations of the low Cu2+ occupancy form of the mammalian prion protein octarepeat region: gaining insight into Cu2+-mediated beta-cleavage.

  2008cited by this paper
• Structure, function and biological relevance of prolyl oligopeptidase.

  2008cited by this paper
• Transmission of bovine spongiform encephalopathy and scrapie to mice

  2007cited by this paper
• Enhanced susceptibility of Prnp‐deficient mice to kainate‐induced seizures, neuronal apoptosis, and death: Role of AMPA/kainate receptors

  2007cited by this paper
• In vitro binding and survival assays of Leishmania parasites to peripherical blood monocytes and monocyte-derived macrophages isolated from dogs naturally and experimentally infected with Leishmania (Leishmania) chagasi

  2007cited by this paper
• A General Model of Prion Strains and Their Pathogenicity

  2007cited by this paper
• Copper and the prion protein: methods, structures, function, and disease.

  2007cited by this paper
• Inherited prion disease with six octapeptide repeat insertional mutation--molecular analysis of phenotypic heterogeneity.

  2006cited by this paper
• Rapid and discriminatory diagnosis of scrapie and BSE in retro-pharyngeal lymph nodes of sheep

  2006cited by this paper
• Reactive Oxygen Species-mediated β-Cleavage of the Prion Protein in the Cellular Response to Oxidative Stress*

  2005cited by this paper
• The octarepeat domain of the prion protein binds Cu(II) with three distinct coordination modes at pH 7.4.

  2005cited by this paper
• Reactive oxygen species-mediated beta-cleavage of the prion protein in the cellular response to oxidative stress.

  2005cited by this paper
• Screening of 145 Anti-PrP Monoclonal Antibodies for Their Capacity to Inhibit PrPSc Replication in Infected Cells*

  2005influential reference
• The N‐terminal cleavage of cellular prion protein in the human brain

  2005cited by this paper
• Diagnosis of human prion disease.

  2005cited by this paper
• 8 Knockouts, Knockins, Transgenics, and Transplants in Prion Research

  2004cited by this paper
• Synthetic Mammalian Prions

  2004cited by this paper
• Glycan-Controlled Epitopes of Prion Protein Include a Major Determinant of Susceptibility to Sheep Scrapie

  2004cited by this paper
• Calpain-dependent Endoproteolytic Cleavage of PrPSc Modulates Scrapie Prion Propagation*

  2004cited by this paper
• Copper binding in the prion protein.

  2004cited by this paper
• Alpha‐ and beta‐ cleavages of the amino‐terminus of the cellular prion protein

  2004cited by this paper
• Upregulation of cellular prion protein (PrPc) after focal cerebral ischemia and influence of lesion severity.

  2004cited by this paper
• Bioassays for Prions

  2004cited by this paper
• The mechanism of internalization of glycosylphosphatidylinositol‐anchored prion protein

  2003cited by this paper
• A quantitative, highly sensitive cell-based infectivity assay for mouse scrapie prions

  2003cited by this paper
• Mapping Cu(II) Binding Sites in Prion Proteins by Diethyl Pyrocarbonate Modification and Matrix-assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometric Footprinting*

  2002cited by this paper
• Cellular prion protein transduces neuroprotective signals

  2002cited by this paper
• PrPC Directly Interacts with Proteins Involved in Signaling Pathways*

  2001cited by this paper
• Hyaluronic Acid Induces Survival and Proliferation of Human Myeloma Cells through an Interleukin-6-mediated Pathway Involving the Phosphorylation of Retinoblastoma Protein*

  2001cited by this paper
• Huntington disease phenocopy is a familial prion disease.

  2001cited by this paper
• Location and properties of metal-binding sites on the human prion protein

  2001cited by this paper
• The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein.

  2001cited by this paper
• Prion Protein Binds Copper within the Physiological Concentration Range*

  2001cited by this paper
• Cleavage of the Amino Terminus of the Prion Protein by Reactive Oxygen Species*

  2001influential reference
• Signal transduction through prion protein.

  2000cited by this paper
• Phorbol Ester-regulated Cleavage of Normal Prion Protein in HEK293 Human Cells and Murine Neurons*

  2000cited by this paper
• Copper(II)-induced Conformational Changes and Protease Resistance in Recombinant and Cellular PrP

  2000cited by this paper
• Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice.

  2000influential reference
• Prion protein of 106 residues creates an artifical transmission barrier for prion replication in transgenic mice.

  1999cited by this paper
• Prions prevent neuronal cell-line death

  1999cited by this paper
• Copper binding to the prion protein: structural implications of four identical cooperative binding sites.

  1999cited by this paper
• Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene.

  1999cited by this paper
• 3 Bioassays of Prions

  1999cited by this paper
• A mouse prion protein transgene rescues mice deficient for the prion protein gene from purkinje cell degeneration and demyelination.

  1999influential reference
• Evidence of Presynaptic Location and Function of the Prion Protein

  1999cited by this paper
• Prion biology and diseases.

  1999cited by this paper
• Prion protein selectively binds copper(II) ions.

  1998cited by this paper
• Endogenous proteolytic cleavage of normal and disease-associated isoforms of the human prion protein in neural and non-neural tissues.

  1998cited by this paper
• Copper Stimulates Endocytosis of the Prion Protein*

  1998cited by this paper
• Transmission of the BSE Agent to Mice in the Absence of Detectable Abnormal Prion Protein

  1997cited by this paper
• Normal host prion protein necessary for scrapie-induced neurotoxicity

  1996cited by this paper
• Prion protein (PrP) with amino‐proximal deletions restoring susceptibility of PrP knockout mice to scrapie.

  1996influential reference
• A vector for expressing foreign genes in the brains and hearts of transgenic mice.

  1996cited by this paper
• Truncated Forms of the Human Prion Protein in Normal Brain and in Prion Diseases (*)

  1995influential reference
• High Prion and PrPSc Levels but Delayed Onset of Disease in Scrapie-Inoculated Mice Heterozygous for a Disrupted PrP Gene

  1994cited by this paper
• Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice.

  1994cited by this paper
• Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins.

  1994cited by this paper
• Inherited prion disease.

  1993cited by this paper
• Transmission of bovine spongiform encephalopathy and scrapie to mice.

  1992cited by this paper
• Synthesis and trafficking of prion proteins in cultured cells.

  1992cited by this paper
• Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene.

  1991cited by this paper
• Prions are novel infectious pathogens causing scrapie and Creutzfeldt-Jakob disease.

  1986cited by this paper
• Pathogenesis of scrapie: study of the temporal development of clinical symptoms, of infectivity titres and scrapie-associated fibrils in brains of hamsters infected intraperitoneally.

  1986cited by this paper
• A cellular gene encodes scrapie PrP 27-30 protein.

  1985cited by this paper
• Purification and structural studies of a major scrapie prion protein.

  1984influential reference
• the original work is properly cited.

  year unknowncited by this paper

• Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion Disease

  2025cites this paper
• Prion diseases: Lessons from historical outbreaks and potential emerging ones

  2025cites this paper
• Liquid–liquid phase separation of the prion protein is regulated by the octarepeat domain independently of histidines and copper

  2024cites this paper
• Copper coordination modulates prion conversion and infectivity in mammalian prion proteins

  2023cites this paper
• Application of N-Terminal Labeling Methods Provide Novel Insights into Endoproteolysis of the Prion Protein in Vivo

  2023cites this paper
• Beta-endoproteolysis of the cellular prion protein by dipeptidyl peptidase-4 and fibroblast activation protein

  2022cites this paper
• Prion protein with a mutant N-terminal octarepeat region undergoes cobalamin-dependent assembly into high–molecular weight complexes

  2022influential citation
• Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

  2022cites this paper
• NMDA receptor misalignment in iPSC-derived neurons from a multi-generational family with inherited Creutzfeldt-Jakob disease

  2022cites this paper
• Investigating CRISPR/Cas9 gene drive for production of disease-preventing prion gene alleles

  2022cites this paper
• An iPSC library from a family with Creutzfeldt-Jakob disease caused by the E200K mutation

  2022cites this paper
• Electrochemical biosensors for biometal-protein interactions in neurodegenerative diseases.

  2021cites this paper
• PrPC as a Transducer of Physiological and Pathological Signals

  2021influential citation
• Liquid–liquid phase separation of full-length prion protein initiates conformational conversion in vitro

  2020cites this paper
• Chronic wasting disease (CWD) prion strains evolve via adaptive diversification of conformers in hosts expressing prion protein polymorphisms

  2020cites this paper
• Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

  2020cites this paper
• Show Me Your Friends and I Tell You Who You Are: The Many Facets of Prion Protein in Stroke

  2020cites this paper
• ODiNPred: comprehensive prediction of protein order and disorder

  2020cites this paper
• Quaternary Structure Changes for PrPSc Predate PrPC Downregulation and Neuronal Death During Progression of Experimental Scrapie Disease

  2020cites this paper
• Phase transition of prion protein initiates proteinase K resistant amyloid formation

  2020cites this paper
• Copper Binding Regulates Cellular Prion Protein Function

  2019cites this paper
• Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review

  2019cites this paper
• Interaction of Peptide Aptamers with Prion Protein Central Domain Promotes α-Cleavage of PrPC

  2018cites this paper
• Application of high-throughput, capillary-based Western analysis to modulated cleavage of the cellular prion protein

  2018cites this paper
• A novel Gerstmann-Sträussler-Scheinker disease mutation defines a precursor for amyloidogenic 8 kDa PrP fragments and reveals N-terminal structural changes shared by other GSS alleles

  2018cites this paper
• Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice

  2017cites this paper
• Diverse functions of the prion protein - Does proteolytic processing hold the key?

  2017cites this paper
• The secret life of extracellular vesicles in metal homeostasis and neurodegeneration

  2015cites this paper
• Subcellular distribution of the prion protein in sickness and in health.

  2015cites this paper
• Neuroprotective properties of the PrP-like Shadoo glycoprotein assessed in the middle cerebral artery occlusion model of ischemia

  2015cites this paper
• PrP charge structure encodes interdomain interactions

  2015cites this paper
• Prion Infectivity Plateaus and Conversion to Symptomatic Disease Originate from Falling Precursor Levels and Increased Levels of Oligomeric PrPSc Species

  2015cites this paper
• Ultrafast photoinduced processes in metal - containing molecular complexes and in proteins

  2015cites this paper