The Interplay of Glycosylation and Disulfide Formation Influences Fibrillization in a Prion Protein Fragment
It is now accepted that the structural transition from cellular prion protein (PrPC) to proteinase K-resistant prion protein scrapie (PrPSc) is the major event leading to transmissible spongiform encephalopathies. Although the mechanism of this transition remains elusive, glycosylation has been prop...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2003-06, Vol.100 (13), p.7593-7598 |
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| creator | Bosques, Carlos J. Imperiali, Barbara |
| description | It is now accepted that the structural transition from cellular prion protein (PrPC) to proteinase K-resistant prion protein scrapie (PrPSc) is the major event leading to transmissible spongiform encephalopathies. Although the mechanism of this transition remains elusive, glycosylation has been proposed to impede the PrPCto PrPScconversion. To address the role of glycosylation, we have prepared glycosylated and unglycosylated peptides derived from the 175-195 fragment of the human prion protein. Comparison of the structure, aggregation kinetics, fibril formation capabilities, and redox susceptibility of Cys-179 has shown that the N-linked glycan (at Asn-181) significantly reduces the rate of fibrillization by promoting intermolecular disulfide formation via Cys-179. Furthermore, the aggressive fibrillization of a C179S mutant of this fragment highlights the significant role of disulfide stability in retarding the rate of fibril formation. The implications of these studies are discussed in the context of fibril formation in the intact prion protein. |
| doi_str_mv | 10.1073/pnas.1232504100 |
| format | Article |
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Although the mechanism of this transition remains elusive, glycosylation has been proposed to impede the PrPCto PrPScconversion. To address the role of glycosylation, we have prepared glycosylated and unglycosylated peptides derived from the 175-195 fragment of the human prion protein. Comparison of the structure, aggregation kinetics, fibril formation capabilities, and redox susceptibility of Cys-179 has shown that the N-linked glycan (at Asn-181) significantly reduces the rate of fibrillization by promoting intermolecular disulfide formation via Cys-179. Furthermore, the aggressive fibrillization of a C179S mutant of this fragment highlights the significant role of disulfide stability in retarding the rate of fibril formation. The implications of these studies are discussed in the context of fibril formation in the intact prion protein.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1232504100</identifier><identifier>PMID: 12805563</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Aggregation ; Amino Acid Sequence ; Biological Sciences ; Cellular biology ; Circular Dichroism ; Congo Red - pharmacology ; Disulfides ; Disulfides - chemistry ; Dithiothreitol - pharmacology ; Glycopeptides ; Glycosylation ; Humans ; Imperialism ; Kinetics ; Line spectra ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Microscopy, Electron ; Models, Biological ; Molecular Sequence Data ; Mutation ; Oxidation-Reduction ; Peptides - chemistry ; Phosphates ; Polysaccharides - chemistry ; Prions ; Prions - chemistry ; Protein Binding ; Proteins ; PrP 27-30 Protein - chemistry ; PrP 27-30 Protein - metabolism ; Solar fibrils ; Spectroscopy ; Spectroscopy, Fourier Transform Infrared ; Studies ; Time Factors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2003-06, Vol.100 (13), p.7593-7598</ispartof><rights>Copyright 1993-2003 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jun 24, 2003</rights><rights>Copyright © 2003, The National Academy of Sciences 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c590t-7b629980d96b91420d9ab9aedf12419d15b0623037625556f9dd03cdd7d8ad5d3</citedby><cites>FETCH-LOGICAL-c590t-7b629980d96b91420d9ab9aedf12419d15b0623037625556f9dd03cdd7d8ad5d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/100/13.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3139791$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3139791$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12805563$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bosques, Carlos J.</creatorcontrib><creatorcontrib>Imperiali, Barbara</creatorcontrib><title>The Interplay of Glycosylation and Disulfide Formation Influences Fibrillization in a Prion Protein Fragment</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>It is now accepted that the structural transition from cellular prion protein (PrPC) to proteinase K-resistant prion protein scrapie (PrPSc) is the major event leading to transmissible spongiform encephalopathies. Although the mechanism of this transition remains elusive, glycosylation has been proposed to impede the PrPCto PrPScconversion. To address the role of glycosylation, we have prepared glycosylated and unglycosylated peptides derived from the 175-195 fragment of the human prion protein. Comparison of the structure, aggregation kinetics, fibril formation capabilities, and redox susceptibility of Cys-179 has shown that the N-linked glycan (at Asn-181) significantly reduces the rate of fibrillization by promoting intermolecular disulfide formation via Cys-179. Furthermore, the aggressive fibrillization of a C179S mutant of this fragment highlights the significant role of disulfide stability in retarding the rate of fibril formation. The implications of these studies are discussed in the context of fibril formation in the intact prion protein.</description><subject>Aggregation</subject><subject>Amino Acid Sequence</subject><subject>Biological Sciences</subject><subject>Cellular biology</subject><subject>Circular Dichroism</subject><subject>Congo Red - pharmacology</subject><subject>Disulfides</subject><subject>Disulfides - chemistry</subject><subject>Dithiothreitol - pharmacology</subject><subject>Glycopeptides</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>Imperialism</subject><subject>Kinetics</subject><subject>Line spectra</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mass Spectrometry</subject><subject>Microscopy, Electron</subject><subject>Models, Biological</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Oxidation-Reduction</subject><subject>Peptides - chemistry</subject><subject>Phosphates</subject><subject>Polysaccharides - chemistry</subject><subject>Prions</subject><subject>Prions - chemistry</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>PrP 27-30 Protein - chemistry</subject><subject>PrP 27-30 Protein - metabolism</subject><subject>Solar fibrils</subject><subject>Spectroscopy</subject><subject>Spectroscopy, Fourier Transform Infrared</subject><subject>Studies</subject><subject>Time Factors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcFvFCEUxonR2LV69mJ04sF4mfYBw8xw6MFUt27SxB7qmTAD07JhYAXGuP71MplNVz1oQsKD9_s-eO8h9BLDGYaGnu-cjGeYUMKgwgCP0AoDx2VdcXiMVgCkKduKVCfoWYxbAOCshafoBJMWGKvpCtnbe11sXNJhZ-W-8ENxZfe9j3srk_GukE4VH02c7GCULtY-jMv9xg120q7XsVibLhhrzc8lY7KouAlzeBN80vm8DvJu1C49R08GaaN-cdhP0df1p9vLz-X1l6vN5YfrsmccUtl0NeG8BcXrjuOK5EB2XGo1YFJhrjDroCYUaFMTlssYuFJAe6Ua1UrFFD1FF4vvbupGrfr8dJBW7IIZZdgLL434M-PMvbjz3wWuq5rirH930Af_bdIxidHEXlsrnfZTFA2tSO74_0HcNjwvyODbv8Ctn4LLTRAk-1SMAMnQ-QL1wccY9PDwYwxiHreYxy2O486K178XeuQP883AmwMwK4922Y-KhvGZeP9vQgyTtUn_SBl9taDbmHx4YHPDeMMx_QWMW8jt</recordid><startdate>20030624</startdate><enddate>20030624</enddate><creator>Bosques, Carlos J.</creator><creator>Imperiali, Barbara</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20030624</creationdate><title>The Interplay of Glycosylation and Disulfide Formation Influences Fibrillization in a Prion Protein Fragment</title><author>Bosques, Carlos J. ; Imperiali, Barbara</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c590t-7b629980d96b91420d9ab9aedf12419d15b0623037625556f9dd03cdd7d8ad5d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Aggregation</topic><topic>Amino Acid Sequence</topic><topic>Biological Sciences</topic><topic>Cellular biology</topic><topic>Circular Dichroism</topic><topic>Congo Red - pharmacology</topic><topic>Disulfides</topic><topic>Disulfides - chemistry</topic><topic>Dithiothreitol - pharmacology</topic><topic>Glycopeptides</topic><topic>Glycosylation</topic><topic>Humans</topic><topic>Imperialism</topic><topic>Kinetics</topic><topic>Line spectra</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Mass Spectrometry</topic><topic>Microscopy, Electron</topic><topic>Models, Biological</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Oxidation-Reduction</topic><topic>Peptides - chemistry</topic><topic>Phosphates</topic><topic>Polysaccharides - chemistry</topic><topic>Prions</topic><topic>Prions - chemistry</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>PrP 27-30 Protein - chemistry</topic><topic>PrP 27-30 Protein - metabolism</topic><topic>Solar fibrils</topic><topic>Spectroscopy</topic><topic>Spectroscopy, Fourier Transform Infrared</topic><topic>Studies</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bosques, Carlos J.</creatorcontrib><creatorcontrib>Imperiali, Barbara</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bosques, Carlos J.</au><au>Imperiali, Barbara</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Interplay of Glycosylation and Disulfide Formation Influences Fibrillization in a Prion Protein Fragment</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2003-06-24</date><risdate>2003</risdate><volume>100</volume><issue>13</issue><spage>7593</spage><epage>7598</epage><pages>7593-7598</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>It is now accepted that the structural transition from cellular prion protein (PrPC) to proteinase K-resistant prion protein scrapie (PrPSc) is the major event leading to transmissible spongiform encephalopathies. Although the mechanism of this transition remains elusive, glycosylation has been proposed to impede the PrPCto PrPScconversion. To address the role of glycosylation, we have prepared glycosylated and unglycosylated peptides derived from the 175-195 fragment of the human prion protein. Comparison of the structure, aggregation kinetics, fibril formation capabilities, and redox susceptibility of Cys-179 has shown that the N-linked glycan (at Asn-181) significantly reduces the rate of fibrillization by promoting intermolecular disulfide formation via Cys-179. Furthermore, the aggressive fibrillization of a C179S mutant of this fragment highlights the significant role of disulfide stability in retarding the rate of fibril formation. 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| subjects | Aggregation Amino Acid Sequence Biological Sciences Cellular biology Circular Dichroism Congo Red - pharmacology Disulfides Disulfides - chemistry Dithiothreitol - pharmacology Glycopeptides Glycosylation Humans Imperialism Kinetics Line spectra Magnetic Resonance Spectroscopy Mass Spectrometry Microscopy, Electron Models, Biological Molecular Sequence Data Mutation Oxidation-Reduction Peptides - chemistry Phosphates Polysaccharides - chemistry Prions Prions - chemistry Protein Binding Proteins PrP 27-30 Protein - chemistry PrP 27-30 Protein - metabolism Solar fibrils Spectroscopy Spectroscopy, Fourier Transform Infrared Studies Time Factors |
| title | The Interplay of Glycosylation and Disulfide Formation Influences Fibrillization in a Prion Protein Fragment |
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