Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitinprotein ligase with monoubiquitylation capacity
Identifieur interne : 001759 ( Main/Corpus ); précédent : 001758; suivant : 001760Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitinprotein ligase with monoubiquitylation capacity
Auteurs : Cornelia Hampe ; Hector Ardila-Osorio ; Margot Fournier ; Alexis Brice ; Olga CortiSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2006-07-01.
Abstract
Mutations in the parkin gene, encoding an E3 ubiquitinprotein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitinprotein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.
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DOI: 10.1093/hmg/ddl131
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Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitinprotein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Cornelia Hampe</name><affiliations><json:string>Neurologie et Thrapeutique Exprimentale, INSERM U679-Universit Pierre & Marie Curie, Paris VI, Hpital de la Piti-Salptrire, 75013 Paris, France,</json:string></affiliations></json:item><json:item><name>Hector Ardila-Osorio</name><affiliations><json:string>Neurologie et Thrapeutique Exprimentale, INSERM U679-Universit Pierre & Marie Curie, Paris VI, Hpital de la Piti-Salptrire, 75013 Paris, France,</json:string></affiliations></json:item><json:item><name>Margot Fournier</name><affiliations><json:string>Neurologie et Thrapeutique Exprimentale, INSERM U679-Universit Pierre & Marie Curie, Paris VI, Hpital de la Piti-Salptrire, 75013 Paris, France,</json:string></affiliations></json:item><json:item><name>Alexis Brice</name><affiliations><json:string>Neurologie et Thrapeutique Exprimentale, INSERM U679-Universit Pierre & Marie Curie, Paris VI, Hpital de la Piti-Salptrire, 75013 Paris, France,</json:string><json:string>Dpartement de Gntique, Cytogntique et Embryologie, Hpital de la Piti-Salptrire, AP-HP, Paris, France and</json:string><json:string>Fdration de Neurologie, Hpital de la Piti-Salptrire, AP-HP, Paris, France</json:string></affiliations></json:item><json:item><name>Olga Corti</name><affiliations><json:string>Neurologie et Thrapeutique Exprimentale, INSERM U679-Universit Pierre & Marie Curie, Paris VI, Hpital de la Piti-Salptrire, 75013 Paris, France,</json:string><json:string>E-mail: corti@ccr.jussieu.fr</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>ARTICLES</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Mutations in the parkin gene, encoding an E3 ubiquitinprotein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. 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Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitinprotein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. 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Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitinprotein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>ARTICLES</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2006-05-19">Created</change><change when="2006-07-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-15">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/C2088226810B35E94B18ABAA4F4ABE7DE6157305/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddl131</article-id><article-id pub-id-type="publisher-id">ddl131</article-id><article-categories><subj-group><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin–protein ligase with monoubiquitylation capacity</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hampe</surname><given-names>Cornelia</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ardila-Osorio</surname><given-names>Hector</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fournier</surname><given-names>Margot</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Brice</surname><given-names>Alexis</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Corti</surname><given-names>Olga</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Neurologie et Thérapeutique Expérimentale</addr-line>, <institution>INSERM U679-Université Pierre & Marie Curie</institution>, <addr-line>Paris VI</addr-line>, <institution>Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>75013 Paris</addr-line>, <country>France</country>,</aff><aff id="af2"><label>2</label><addr-line>Département de Génétique, Cytogénétique et Embryologie</addr-line>, <institution>Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>AP-HP, Paris</addr-line>, <country>France</country> and</aff><aff id="af3"><label>3</label><addr-line>Fédération de Neurologie</addr-line>, <institution>Hôpital de la Pitié-Salpêtrière</institution>, <addr-line>AP-HP, Paris</addr-line>, <country>France</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed. Tel: <phone>+33 142162217</phone>; fax: <fax>+33 144243658</fax>; Email: <email>corti@ccr.jussieu.fr</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>July</month><year>2006</year></pub-date><pub-date pub-type="epub"><day>19</day><month>5</month><year>2006</year></pub-date><volume>15</volume><issue>13</issue><fpage>2059</fpage><lpage>2075</lpage><history><date date-type="received"><day>26</day><month>1</month><year>2006</year></date><date date-type="rev-recd"><day>4</day><month>4</month><year>2006</year></date><date date-type="accepted"><day>12</day><month>5</month><year>2006</year></date></history><copyright-statement>© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2006</copyright-year><abstract><p>Mutations in the <italic>parkin</italic> gene, encoding an E3 ubiquitin–protein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of <italic>parkin</italic> gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely <italic>in vitro</italic> ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this <italic>in vitro</italic> assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitin–protein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitinprotein ligase with monoubiquitylation capacity</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitinprotein ligase with monoubiquitylation capacity</title></titleInfo><name type="personal"><namePart type="given">Cornelia</namePart><namePart type="family">Hampe</namePart><affiliation>3 Paris, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hector</namePart><namePart type="family">Ardila-Osorio</namePart><affiliation>3 Paris, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Margot</namePart><namePart type="family">Fournier</namePart><affiliation>3 Paris, France,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alexis</namePart><namePart type="family">Brice</namePart><affiliation>3 Paris, France,</affiliation><affiliation></affiliation><affiliation></affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Olga</namePart><namePart type="family">Corti</namePart><affiliation>3 Paris, France,</affiliation><affiliation>E-mail: corti@ccr.jussieu.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>ARTICLES</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2006-07-01</dateIssued><dateCreated encoding="w3cdtf">2006-05-19</dateCreated><copyrightDate encoding="w3cdtf">2006</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Mutations in the parkin gene, encoding an E3 ubiquitinprotein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitinprotein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>15</number></detail><detail type="issue"><caption>no.</caption><number>13</number></detail><extent unit="pages"><start>2059</start><end>2075</end></extent></part></relatedItem><identifier type="istex">C2088226810B35E94B18ABAA4F4ABE7DE6157305</identifier><identifier type="DOI">10.1093/hmg/ddl131</identifier><identifier type="ArticleID">ddl131</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2006. 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