4kml | pdb_00004kml

Probing the N-terminal beta-sheet conversion in the crystal structure of the full-length human prion protein bound to a Nanobody

spinqualitylabelsall models 4kml, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4kml is a 2 chain structure with sequence from Camelus glama and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 4n9o Gene: PRIP, PRNP, PRP (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [PRIO_HUMAN] Note=PrP is found in high quantity in the brain of humans and animals infected with neurodegenerative diseases known as transmissible spongiform encephalopathies or prion diseases, like: Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Straussler disease (GSD), Huntington disease-like type 1 (HDL1) and kuru in humans; scrapie in sheep and goat; bovine spongiform encephalopathy (BSE) in cattle; transmissible mink encephalopathy (TME); chronic wasting disease (CWD) of mule deer and elk; feline spongiform encephalopathy (FSE) in cats and exotic ungulate encephalopathy (EUE) in nyala and greater kudu. The prion diseases illustrate three manifestations of CNS degeneration: (1) infectious (2) sporadic and (3) dominantly inherited forms. TME, CWD, BSE, FSE, EUE are all thought to occur after consumption of prion-infected foodstuffs. Defects in PRNP are the cause of Creutzfeldt-Jakob disease (CJD) [MIM:123400]. CJD occurs primarily as a sporadic disorder (1 per million), while 10-15% are familial. Accidental transmission of CJD to humans appears to be iatrogenic (contaminated human growth hormone (HGH), corneal transplantation, electroencephalographic electrode implantation, etc.). Epidemiologic studies have failed to implicate the ingestion of infected annimal meat in the pathogenesis of CJD in human. The triad of microscopic features that characterize the prion diseases consists of (1) spongiform degeneration of neurons, (2) severe astrocytic gliosis that often appears to be out of proportion to the degree of nerve cell loss, and (3) amyloid plaque formation. CJD is characterized by progressive dementia and myoclonic seizures, affecting adults in mid-life. Some patients present sleep disorders, abnormalities of high cortical function, cerebellar and corticospinal disturbances. The disease ends in death after a 3-12 months illness. Defects in PRNP are the cause of fatal familial insomnia (FFI) [MIM:600072]. FFI is an autosomal dominant disorder and is characterized by neuronal degeneration limited to selected thalamic nuclei and progressive insomnia. Defects in PRNP are the cause of Gerstmann-Straussler disease (GSD) [MIM:137440]. GSD is a heterogeneous disorder and was defined as a spinocerebellar ataxia with dementia and plaquelike deposits. GSD incidence is less than 2 per 100 million live births. Defects in PRNP are the cause of Huntington disease-like type 1 (HDL1) [MIM:603218]. HDL1 is an autosomal dominant, early onset neurodegenerative disorder with prominent psychiatric features. Defects in PRNP are the cause of kuru (KURU) [MIM:245300]. Kuru is transmitted during ritualistic cannibalism, among natives of the New Guinea highlands. Patients exhibit various movement disorders like cerebellar abnormalities, rigidity of the limbs, and clonus. Emotional lability is present, and dementia is conspicuously absent. Death usually occurs from 3 to 12 month after onset. Defects in PRNP are the cause of spongiform encephalopathy with neuropsychiatric features (SENF) [MIM:606688]; an autosomal dominant presenile dementia with a rapidly progressive and protracted clinical course. The dementia was characterized clinically by frontotemporal features, including early personality changes. Some patients had memory loss, several showed aggressiveness, hyperorality and verbal stereotypy, others had parkinsonian symptoms. Function [PRIO_HUMAN] 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 PubMed Prions are fatal neurodegenerative transmissible agents causing several incurable illnesses in humans and animals. Prion diseases are caused by the structural conversion of the cellular prion protein, PrPC, into its misfolded oligomeric form, known as prion or PrPSc. The canonical human PrPC (HuPrP) fold features an unstructured N-terminal part (residues 23-124) and a well-defined C-terminal globular domain (residues 125-231). Compelling evidence indicates that an evolutionary N-terminal conserved motif AGAAAAGA (residues 113-120) plays an important role in the conversion to PrPSc. The intrinsic flexibility of the N-terminal has hampered efforts to obtain detailed atomic information on the structural features of this palindromic region. In this study, we crystallized the full-length HuPrP in complex with a nanobody (Nb484) that inhibits prion propagation. In the complex, the prion protein is unstructured from residue 23 to 116. The palindromic motif adopts a stable and fully extended configuration to form a three-stranded antiparallel beta-sheet with the beta1 and beta2 strands, demonstrating that the full-length HuPrPC can adopt a more elaborate beta0-beta1-alpha1-beta2-alpha2-alpha3 structural organization than the canonical beta1-alpha1-beta2-alpha2-alpha3 prion-like fold. From this structure, it appears that the palindromic motif mediates beta-enrichment in the PrPC monomer as one of the early events in the conversion of PrPC into PrPSc. Probing the N-Terminal beta-Sheet Conversion in the Crystal Structure of the Human Prion Protein Bound to a Nanobody.,Abskharon RN, Giachin G, Wohlkonig A, Soror SH, Pardon E, Legname G, Steyaert J J Am Chem Soc. 2014 Jan 8. PMID:24400836 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Prion

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