Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin
Identifieur interne : 001703 ( Main/Corpus ); précédent : 001702; suivant : 001704Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin
Auteurs : Sathya R. Sriram ; Xiaojie Li ; Han Seok Ko ; Kenny K. K. Chung ; Esther Wong ; Kah Leong Lim ; Valina L. Dawson ; Ted M. DawsonSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2005-09-01.
Abstract
Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.
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DOI: 10.1093/hmg/ddi292
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The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Sathya R. 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A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. 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Mol. Genet.</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2005-09-01"></date><biblScope unit="volume">14</biblScope><biblScope unit="issue">17</biblScope><biblScope unit="page" from="2571">2571</biblScope><biblScope unit="page" to="2586">2586</biblScope></imprint></monogr><idno type="istex">7C61A0EEE6D9282C488F92D5714D42965C021548</idno><idno type="DOI">10.1093/hmg/ddi292</idno><idno type="href">ddi292</idno><idno type="local">ddi292</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2005-07-27</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.</p></abstract></profileDesc><revisionDesc><change when="2005-07-27">Created</change><change when="2005-09-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-3-14">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/7C61A0EEE6D9282C488F92D5714D42965C021548/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</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 xml:lang="en" article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">hmg</journal-id><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">Hum. Mol. Genet.</abbrev-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="other">ddi292</article-id><article-id pub-id-type="doi">10.1093/hmg/ddi292</article-id><article-categories><subj-group subj-group-type="heading"><subject>ARTICLES</subject></subj-group></article-categories><title-group><article-title>Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Sriram</surname><given-names>Sathya R.</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Xiaojie</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Ko</surname><given-names>Han Seok</given-names></name><xref rid="AF1">1</xref><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Chung</surname><given-names>Kenny K.K.</given-names></name><xref rid="AF1">1</xref><xref rid="AF3">3</xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Esther</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Lim</surname><given-names>Kah Leong</given-names></name><xref rid="AF6">6</xref></contrib><contrib contrib-type="author"><name><surname>Dawson</surname><given-names>Valina L.</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref><xref rid="AF3">3</xref><xref rid="AF4">4</xref><xref rid="AF5">5</xref></contrib><contrib contrib-type="author"><name><surname>Dawson</surname><given-names>Ted M.</given-names></name><xref rid="AF1">1</xref><xref rid="AF2">2</xref><xref rid="AF3">3</xref><xref rid="AF4">4</xref><xref rid="COR1">*</xref></contrib><aff id="AF1"><sup>1</sup>Institute for Cell Engineering,</aff><aff id="AF2"><sup>2</sup>Cellular and Molecular Medicine Graduate Program,</aff><aff id="AF3"><sup>3</sup>Department of Neurology and</aff><aff id="AF4"><sup>4</sup>Department of Neuroscience and</aff><aff id="AF5"><sup>5</sup>Department of Physiology Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and</aff><aff id="AF6"><sup>6</sup>Neurodegeneration Laboratory, National Neurosciences Institute, Singapore</aff></contrib-group><author-notes><corresp id="COR1"><label>*</label>To whom correspondence should be addressed at: Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N Broadway Street, Suite 731, Baltimore, MD 21205, USA. Tel: +1 4106143359; Fax: +1 4106149568; Email: <ext-link xlink:href="tdawson@jhmi.edu" ext-link-type="email">tdawson@jhmi.edu</ext-link></corresp></author-notes><pub-date pub-type="epub"><day>27</day><month>07</month><year>2005</year></pub-date><pub-date pub-type="ppub"><day>1</day><month>September</month><year>2005</year></pub-date><volume>14</volume><issue>17</issue><fpage>2571</fpage><lpage>2586</lpage><history><date date-type="accepted"><day>19</day><month>07</month><year>2005</year></date><date date-type="received"><day>12</day><month>05</month><year>2005</year></date></history><permissions><copyright-statement>© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org</copyright-statement><copyright-year>2005</copyright-year></permissions><self-uri content-type="arthw-pdf" xlink:href="ddi292"></self-uri><abstract xml:lang="en"><p>Mutations in <italic>parkin</italic> are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.</p></abstract><custom-meta-wrap><custom-meta><meta-name>hwp-legacy-fpage</meta-name><meta-value>2571</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>1 September 2005</meta-value></custom-meta><custom-meta><meta-name>hwp-legacy-dochead</meta-name><meta-value>ARTICLE</meta-value></custom-meta></custom-meta-wrap></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin</title></titleInfo><name type="personal"><namePart type="given">Sathya R.</namePart><namePart type="family">Sriram</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Cellular and Molecular Medicine Graduate Program,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Xiaojie</namePart><namePart type="family">Li</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Cellular and Molecular Medicine Graduate Program,</affiliation><affiliation>Department of Neurology and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Han Seok</namePart><namePart type="family">Ko</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Department of Neurology and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kenny K.K.</namePart><namePart type="family">Chung</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Department of Neurology and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Esther</namePart><namePart type="family">Wong</namePart><affiliation>Neurodegeneration Laboratory, National Neurosciences Institute, Singapore</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kah Leong</namePart><namePart type="family">Lim</namePart><affiliation>Neurodegeneration Laboratory, National Neurosciences Institute, Singapore</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Valina L.</namePart><namePart type="family">Dawson</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Cellular and Molecular Medicine Graduate Program,</affiliation><affiliation>Department of Neurology and</affiliation><affiliation>Department of Neuroscience and</affiliation><affiliation>Department of Physiology Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ted M.</namePart><namePart type="family">Dawson</namePart><affiliation>Institute for Cell Engineering,</affiliation><affiliation>Cellular and Molecular Medicine Graduate Program,</affiliation><affiliation>Department of Neurology and</affiliation><affiliation>Department of Neuroscience and</affiliation><affiliation>E-mail: tdawson@jhmi.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2005-09-01</dateIssued><dateCreated encoding="w3cdtf">2005-07-27</dateCreated><copyrightDate encoding="w3cdtf">2005</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 lang="en">Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.</abstract><note type="author-notes">*To whom correspondence should be addressed at: Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N Broadway Street, Suite 731, Baltimore, MD 21205, USA. Tel: +1 4106143359; Fax: +1 4106149568; Email: tdawson@jhmi.edu</note><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><titleInfo type="abbreviated"><title>Hum. Mol. Genet.</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><identifier type="PublisherID-nlm-ta">Hum Mol Genet</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>14</number></detail><detail type="issue"><caption>no.</caption><number>17</number></detail><extent unit="pages"><start>2571</start><end>2586</end></extent></part></relatedItem><identifier type="istex">7C61A0EEE6D9282C488F92D5714D42965C021548</identifier><identifier type="DOI">10.1093/hmg/ddi292</identifier><identifier type="href">ddi292</identifier><identifier type="local">ddi292</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author 2005. Published by Oxford University Press. All rights reserved. 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