2m8t
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | + | ==Solution NMR structure of the V209M variant of the human prion protein (residues 90-231)== | |
| - | + | <StructureSection load='2m8t' size='340' side='right' caption='[[2m8t]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[2m8t]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2M8T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2M8T FirstGlance]. <br> | |
| - | ==Disease== | + | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRIP, PRNP, PRP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2m8t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2m8t OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2m8t RCSB], [http://www.ebi.ac.uk/pdbsum/2m8t PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
[[http://www.uniprot.org/uniprot/PRIO_HUMAN 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.<ref>PMID:19936054</ref> <ref>PMID:1671440</ref> <ref>PMID:1975028</ref> <ref>PMID:8461023</ref> <ref>PMID:7902693</ref> <ref>PMID:7906019</ref> <ref>PMID:7913755</ref> <ref>PMID:8909447</ref> <ref>PMID:9266722</ref> <ref>PMID:10790216</ref> Defects in PRNP are the cause of Creutzfeldt-Jakob disease (CJD) [MIM:[http://omim.org/entry/123400 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.<ref>PMID:19936054</ref> <ref>PMID:1671440</ref> <ref>PMID:1975028</ref> <ref>PMID:8461023</ref> <ref>PMID:7902693</ref> <ref>PMID:7906019</ref> <ref>PMID:7913755</ref> <ref>PMID:8909447</ref> <ref>PMID:9266722</ref> <ref>PMID:10790216</ref> Defects in PRNP are the cause of fatal familial insomnia (FFI) [MIM:[http://omim.org/entry/600072 600072]]. FFI is an autosomal dominant disorder and is characterized by neuronal degeneration limited to selected thalamic nuclei and progressive insomnia.<ref>PMID:19936054</ref> <ref>PMID:19927125</ref> <ref>PMID:1347910</ref> Defects in PRNP are the cause of Gerstmann-Straussler disease (GSD) [MIM:[http://omim.org/entry/137440 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.<ref>PMID:19936054</ref> <ref>PMID:19927125</ref> <ref>PMID:10581485</ref> <ref>PMID:2564168</ref> <ref>PMID:1363810</ref> <ref>PMID:7902972</ref> <ref>PMID:7699395</ref> <ref>PMID:7783876</ref> <ref>PMID:8797472</ref> <ref>PMID:9786248</ref> <ref>PMID:11709001</ref> Defects in PRNP are the cause of Huntington disease-like type 1 (HDL1) [MIM:[http://omim.org/entry/603218 603218]]. HDL1 is an autosomal dominant, early onset neurodegenerative disorder with prominent psychiatric features.<ref>PMID:19936054</ref> Defects in PRNP are the cause of kuru (KURU) [MIM:[http://omim.org/entry/245300 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.<ref>PMID:19936054</ref> Defects in PRNP are the cause of spongiform encephalopathy with neuropsychiatric features (SENF) [MIM:[http://omim.org/entry/606688 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.<ref>PMID:19936054</ref> | [[http://www.uniprot.org/uniprot/PRIO_HUMAN 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.<ref>PMID:19936054</ref> <ref>PMID:1671440</ref> <ref>PMID:1975028</ref> <ref>PMID:8461023</ref> <ref>PMID:7902693</ref> <ref>PMID:7906019</ref> <ref>PMID:7913755</ref> <ref>PMID:8909447</ref> <ref>PMID:9266722</ref> <ref>PMID:10790216</ref> Defects in PRNP are the cause of Creutzfeldt-Jakob disease (CJD) [MIM:[http://omim.org/entry/123400 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.<ref>PMID:19936054</ref> <ref>PMID:1671440</ref> <ref>PMID:1975028</ref> <ref>PMID:8461023</ref> <ref>PMID:7902693</ref> <ref>PMID:7906019</ref> <ref>PMID:7913755</ref> <ref>PMID:8909447</ref> <ref>PMID:9266722</ref> <ref>PMID:10790216</ref> Defects in PRNP are the cause of fatal familial insomnia (FFI) [MIM:[http://omim.org/entry/600072 600072]]. FFI is an autosomal dominant disorder and is characterized by neuronal degeneration limited to selected thalamic nuclei and progressive insomnia.<ref>PMID:19936054</ref> <ref>PMID:19927125</ref> <ref>PMID:1347910</ref> Defects in PRNP are the cause of Gerstmann-Straussler disease (GSD) [MIM:[http://omim.org/entry/137440 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.<ref>PMID:19936054</ref> <ref>PMID:19927125</ref> <ref>PMID:10581485</ref> <ref>PMID:2564168</ref> <ref>PMID:1363810</ref> <ref>PMID:7902972</ref> <ref>PMID:7699395</ref> <ref>PMID:7783876</ref> <ref>PMID:8797472</ref> <ref>PMID:9786248</ref> <ref>PMID:11709001</ref> Defects in PRNP are the cause of Huntington disease-like type 1 (HDL1) [MIM:[http://omim.org/entry/603218 603218]]. HDL1 is an autosomal dominant, early onset neurodegenerative disorder with prominent psychiatric features.<ref>PMID:19936054</ref> Defects in PRNP are the cause of kuru (KURU) [MIM:[http://omim.org/entry/245300 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.<ref>PMID:19936054</ref> Defects in PRNP are the cause of spongiform encephalopathy with neuropsychiatric features (SENF) [MIM:[http://omim.org/entry/606688 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.<ref>PMID:19936054</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PRIO_HUMAN 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).<ref>PMID:12732622</ref> <ref>PMID:19936054</ref> <ref>PMID:20564047</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Prion diseases, or transmissible spongiform encephalopathies (TSEs), are associated with the conformational conversion of the cellular prion protein, PrP(C), into a protease-resistant form, PrP(Sc). Here, we show that mutation-induced thermodynamic stabilization of the folded, alpha-helical domain of PrP(C) has a dramatic inhibitory effect on the conformational conversion of prion protein in vitro, as well as on the propagation of TSE disease in vivo. Transgenic mice expressing a human prion protein variant with increased thermodynamic stability were found to be much more resistant to infection with the TSE agent than those expressing wild-type human prion protein, in both the primary passage and three subsequent subpassages. These findings not only provide a line of evidence in support of the protein-only model of TSEs but also yield insight into the molecular nature of the PrP(C)-->PrP(Sc) conformational transition, and they suggest an approach to the treatment of prion diseases. | ||
| - | + | Thermodynamic Stabilization of the Folded Domain of Prion Protein Inhibits Prion Infection in Vivo.,Kong Q, Mills JL, Kundu B, Li X, Qing L, Surewicz K, Cali I, Huang S, Zheng M, Swietnicki W, Sonnichsen FD, Gambetti P, Surewicz WK Cell Rep. 2013 Jul 25;4(2):248-54. doi: 10.1016/j.celrep.2013.06.030. Epub 2013, Jul 18. PMID:23871665<ref>PMID:23871665</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | == | + | ==See Also== |
| - | + | *[[Prion|Prion]] | |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| - | [[Category: Mills, J L | + | [[Category: Mills, J L]] |
| - | [[Category: Soennichsen, F D | + | [[Category: Soennichsen, F D]] |
| - | [[Category: Surewicz, K | + | [[Category: Surewicz, K]] |
| - | [[Category: Surewicz, W | + | [[Category: Surewicz, W]] |
[[Category: Cell cycle]] | [[Category: Cell cycle]] | ||
[[Category: Membrane protein]] | [[Category: Membrane protein]] | ||
Revision as of 11:31, 18 December 2014
Solution NMR structure of the V209M variant of the human prion protein (residues 90-231)
| |||||||||||
