Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization.
Identifieur interne : 000272 ( PubMed/Checkpoint ); précédent : 000271; suivant : 000273Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization.
Auteurs : Filsy Samuel [Canada] ; William P. Flavin ; Sobia Iqbal [Canada] ; Consiglia Pacelli ; Sri Dushyaanthan Sri Renganathan [Canada] ; Louis-Eric Trudeau ; Edward M. Campbell [États-Unis] ; Paul E. Fraser [Canada] ; Anurag Tandon [Canada]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2016.
English descriptors
- KwdEn :
- Amino Acid Substitution, Animals, Animals, Newborn, Cell Line, Cells, Cultured, Dopaminergic Neurons (cytology), Dopaminergic Neurons (metabolism), Dopaminergic Neurons (pathology), Endocytosis, Humans, Mesencephalon (cytology), Mesencephalon (metabolism), Mesencephalon (pathology), Mice, Mutation, Parkinson Disease (genetics), Parkinson Disease (metabolism), Parkinson Disease (pathology), Phosphorylation, Protein Aggregation, Pathological (genetics), Protein Aggregation, Pathological (metabolism), Protein Aggregation, Pathological (pathology), Protein Folding, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases (genetics), Protein-Serine-Threonine Kinases (metabolism), Recombinant Fusion Proteins (genetics), Recombinant Fusion Proteins (metabolism), Recombinant Proteins (chemistry), Recombinant Proteins (genetics), Recombinant Proteins (metabolism), Serine (metabolism), Synaptosomes (metabolism), Synaptosomes (pathology), alpha-Synuclein (chemistry), alpha-Synuclein (genetics), alpha-Synuclein (metabolism).
- MESH :
- chemical , chemistry : Recombinant Proteins, alpha-Synuclein.
- chemical , genetics : Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Recombinant Proteins, alpha-Synuclein.
- cytology : Dopaminergic Neurons, Mesencephalon.
- genetics : Parkinson Disease, Protein Aggregation, Pathological.
- metabolism : Dopaminergic Neurons, Mesencephalon, Parkinson Disease, Protein Aggregation, Pathological, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Recombinant Proteins, Serine, Synaptosomes, alpha-Synuclein.
- pathology : Dopaminergic Neurons, Mesencephalon, Parkinson Disease, Protein Aggregation, Pathological, Synaptosomes.
- Amino Acid Substitution, Animals, Animals, Newborn, Cell Line, Cells, Cultured, Endocytosis, Humans, Mice, Mutation, Phosphorylation, Protein Folding, Protein Processing, Post-Translational.
Abstract
Although trace levels of phosphorylated α-synuclein (α-syn) are detectable in normal brains, nearly all α-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on α-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of α-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated α-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated α-syn isoforms were detected earlier, although the fibrils remained phosphatase- and protease-sensitive. Membrane binding of α-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT α-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P α-syn binding was greatly increased, and A53T α-syn was slightly lower, implicating distal effects of the carboxyl- on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of α-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated α-syn isoforms, a potential means for misfolded extracellular or lumenal α-syn to access cytosolic α-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of α-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of α-syn misfolding.
DOI: 10.1074/jbc.M115.705095
PubMed: 26719332
Affiliations:
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Flavin</name><affiliation><nlm:affiliation>the Integrative Cell Biology Program.</nlm:affiliation><wicri:noCountry code="no comma">the Integrative Cell Biology Program.</wicri:noCountry></affiliation></author><author><name sortKey="Iqbal, Sobia" sort="Iqbal, Sobia" uniqKey="Iqbal S" first="Sobia" last="Iqbal">Sobia Iqbal</name><affiliation wicri:level="4"><nlm:affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Pacelli, Consiglia" sort="Pacelli, Consiglia" uniqKey="Pacelli C" first="Consiglia" last="Pacelli">Consiglia Pacelli</name><affiliation><nlm:affiliation>the Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Québec H4T 1J4, Canada, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Sri Renganathan, Sri Dushyaanthan" sort="Sri Renganathan, Sri Dushyaanthan" uniqKey="Sri Renganathan S" first="Sri Dushyaanthan" last="Sri Renganathan">Sri Dushyaanthan Sri Renganathan</name><affiliation wicri:level="4"><nlm:affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Trudeau, Louis Eric" sort="Trudeau, Louis Eric" uniqKey="Trudeau L" first="Louis-Eric" last="Trudeau">Louis-Eric Trudeau</name><affiliation><nlm:affiliation>the Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Québec H4T 1J4, Canada, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Campbell, Edward M" sort="Campbell, Edward M" uniqKey="Campbell E" first="Edward M" last="Campbell">Edward M. Campbell</name><affiliation wicri:level="2"><nlm:affiliation>the Integrative Cell Biology Program, Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Illinois</region></placeName><wicri:cityArea>the Integrative Cell Biology Program, Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood</wicri:cityArea></affiliation></author><author><name sortKey="Fraser, Paul E" sort="Fraser, Paul E" uniqKey="Fraser P" first="Paul E" last="Fraser">Paul E. Fraser</name><affiliation wicri:level="4"><nlm:affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, the Departments of Medical Biophysics and.</nlm:affiliation><orgName type="university">Université de Toronto</orgName><country>Canada</country><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author><author><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name><affiliation wicri:level="4"><nlm:affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, Medicine, University of Toronto, Toronto, Ontario M5T 2S8, Canada a.tandon@utoronto.ca.</nlm:affiliation><country wicri:rule="url">Canada</country><wicri:regionArea>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, Medicine, University of Toronto, Toronto, Ontario M5T 2S8</wicri:regionArea><orgName type="university">Université de Toronto</orgName><placeName><settlement type="city">Toronto</settlement><region type="state">Ontario</region></placeName></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Substitution</term><term>Animals</term><term>Animals, Newborn</term><term>Cell Line</term><term>Cells, Cultured</term><term>Dopaminergic Neurons (cytology)</term><term>Dopaminergic Neurons (metabolism)</term><term>Dopaminergic Neurons (pathology)</term><term>Endocytosis</term><term>Humans</term><term>Mesencephalon (cytology)</term><term>Mesencephalon (metabolism)</term><term>Mesencephalon (pathology)</term><term>Mice</term><term>Mutation</term><term>Parkinson Disease (genetics)</term><term>Parkinson Disease (metabolism)</term><term>Parkinson Disease (pathology)</term><term>Phosphorylation</term><term>Protein Aggregation, Pathological (genetics)</term><term>Protein Aggregation, Pathological (metabolism)</term><term>Protein Aggregation, Pathological (pathology)</term><term>Protein Folding</term><term>Protein Processing, Post-Translational</term><term>Protein-Serine-Threonine Kinases (genetics)</term><term>Protein-Serine-Threonine Kinases (metabolism)</term><term>Recombinant Fusion Proteins (genetics)</term><term>Recombinant Fusion Proteins (metabolism)</term><term>Recombinant Proteins (chemistry)</term><term>Recombinant Proteins (genetics)</term><term>Recombinant Proteins (metabolism)</term><term>Serine (metabolism)</term><term>Synaptosomes (metabolism)</term><term>Synaptosomes (pathology)</term><term>alpha-Synuclein (chemistry)</term><term>alpha-Synuclein (genetics)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Recombinant Proteins</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Protein-Serine-Threonine Kinases</term><term>Recombinant Fusion Proteins</term><term>Recombinant Proteins</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Dopaminergic Neurons</term><term>Mesencephalon</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Parkinson Disease</term><term>Protein Aggregation, Pathological</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Dopaminergic Neurons</term><term>Mesencephalon</term><term>Parkinson Disease</term><term>Protein Aggregation, Pathological</term><term>Protein-Serine-Threonine Kinases</term><term>Recombinant Fusion Proteins</term><term>Recombinant Proteins</term><term>Serine</term><term>Synaptosomes</term><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Dopaminergic Neurons</term><term>Mesencephalon</term><term>Parkinson Disease</term><term>Protein Aggregation, Pathological</term><term>Synaptosomes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term><term>Animals</term><term>Animals, Newborn</term><term>Cell Line</term><term>Cells, Cultured</term><term>Endocytosis</term><term>Humans</term><term>Mice</term><term>Mutation</term><term>Phosphorylation</term><term>Protein Folding</term><term>Protein Processing, Post-Translational</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Although trace levels of phosphorylated α-synuclein (α-syn) are detectable in normal brains, nearly all α-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on α-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of α-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated α-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated α-syn isoforms were detected earlier, although the fibrils remained phosphatase- and protease-sensitive. Membrane binding of α-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT α-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P α-syn binding was greatly increased, and A53T α-syn was slightly lower, implicating distal effects of the carboxyl- on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of α-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated α-syn isoforms, a potential means for misfolded extracellular or lumenal α-syn to access cytosolic α-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of α-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of α-syn misfolding.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26719332</PMID><DateCreated><Year>2016</Year><Month>02</Month><Day>27</Day></DateCreated><DateCompleted><Year>2016</Year><Month>08</Month><Day>01</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>26</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1083-351X</ISSN><JournalIssue CitedMedium="Internet"><Volume>291</Volume><Issue>9</Issue><PubDate><Year>2016</Year><Month>Feb</Month><Day>26</Day></PubDate></JournalIssue><Title>The Journal of biological chemistry</Title><ISOAbbreviation>J. Biol. Chem.</ISOAbbreviation></Journal><ArticleTitle>Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization.</ArticleTitle><Pagination><MedlinePgn>4374-85</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1074/jbc.M115.705095</ELocationID><Abstract><AbstractText>Although trace levels of phosphorylated α-synuclein (α-syn) are detectable in normal brains, nearly all α-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on α-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of α-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated α-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated α-syn isoforms were detected earlier, although the fibrils remained phosphatase- and protease-sensitive. Membrane binding of α-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT α-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P α-syn binding was greatly increased, and A53T α-syn was slightly lower, implicating distal effects of the carboxyl- on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of α-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated α-syn isoforms, a potential means for misfolded extracellular or lumenal α-syn to access cytosolic α-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of α-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of α-syn misfolding.</AbstractText><CopyrightInformation>© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Samuel</LastName><ForeName>Filsy</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Flavin</LastName><ForeName>William P</ForeName><Initials>WP</Initials><AffiliationInfo><Affiliation>the Integrative Cell Biology Program.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Iqbal</LastName><ForeName>Sobia</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pacelli</LastName><ForeName>Consiglia</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>the Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Québec H4T 1J4, Canada, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sri Renganathan</LastName><ForeName>Sri Dushyaanthan</ForeName><Initials>SD</Initials><AffiliationInfo><Affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Trudeau</LastName><ForeName>Louis-Eric</ForeName><Initials>LE</Initials><AffiliationInfo><Affiliation>the Departments of Pharmacology and Neurosciences, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Université de Montréal, Québec H4T 1J4, Canada, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Campbell</LastName><ForeName>Edward M</ForeName><Initials>EM</Initials><AffiliationInfo><Affiliation>the Integrative Cell Biology Program, Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fraser</LastName><ForeName>Paul E</ForeName><Initials>PE</Initials><AffiliationInfo><Affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, the Departments of Medical Biophysics and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tandon</LastName><ForeName>Anurag</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>From the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T 2S8, Canada, Medicine, University of Toronto, Toronto, Ontario M5T 2S8, Canada a.tandon@utoronto.ca.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>MOP-115056</GrantID><Agency>Canadian Institutes of Health Research</Agency><Country>Canada</Country></Grant><Grant><GrantID>MOP-84501</GrantID><Agency>Canadian Institutes of Health Research</Agency><Country>Canada</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>12</Month><Day>30</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Biol Chem</MedlineTA><NlmUniqueID>2985121R</NlmUniqueID><ISSNLinking>0021-9258</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011993">Recombinant Fusion Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011994">Recombinant Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C497604">SNCA protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051844">alpha-Synuclein</NameOfSubstance></Chemical><Chemical><RegistryNumber>452VLY9402</RegistryNumber><NameOfSubstance UI="D012694">Serine</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.-</RegistryNumber><NameOfSubstance UI="C496126">PLK2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D017346">Protein-Serine-Threonine Kinases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):763-8</RefSource><PMID Version="1">18178617</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Neurosci. 2005 Jun 8;25(23):5544-52</RefSource><PMID Version="1">15944382</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>EMBO Rep. 2002 Jun;3(6):583-8</RefSource><PMID Version="1">12034752</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Mol Neurobiol. 2013 Apr;47(2):509-24</RefSource><PMID Version="1">22923347</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20051-6</RefSource><PMID 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MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC4813466 [Available on 02/26/17]</OtherID><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Parkinson disease</Keyword><Keyword MajorTopicYN="N">endocytosis</Keyword><Keyword MajorTopicYN="N">fibril</Keyword><Keyword MajorTopicYN="N">post-translational modification (PTM)</Keyword><Keyword MajorTopicYN="N">protein kinase</Keyword><Keyword MajorTopicYN="N">protein misfolding</Keyword><Keyword MajorTopicYN="N">protein self-assembly</Keyword><Keyword MajorTopicYN="N">vesicles</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>11</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="pmc-release"><Year>2017</Year><Month>02</Month><Day>26</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>1</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>1</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2016</Year><Month>8</Month><Day>2</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26719332</ArticleId><ArticleId IdType="pii">M115.705095</ArticleId><ArticleId IdType="doi">10.1074/jbc.M115.705095</ArticleId><ArticleId IdType="pmc">PMC4813466</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Illinois</li><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><name sortKey="Flavin, William P" sort="Flavin, William P" uniqKey="Flavin W" first="William P" last="Flavin">William P. Flavin</name><name sortKey="Pacelli, Consiglia" sort="Pacelli, Consiglia" uniqKey="Pacelli C" first="Consiglia" last="Pacelli">Consiglia Pacelli</name><name sortKey="Trudeau, Louis Eric" sort="Trudeau, Louis Eric" uniqKey="Trudeau L" first="Louis-Eric" last="Trudeau">Louis-Eric Trudeau</name></noCountry><country name="Canada"><region name="Ontario"><name sortKey="Samuel, Filsy" sort="Samuel, Filsy" uniqKey="Samuel F" first="Filsy" last="Samuel">Filsy Samuel</name></region><name sortKey="Fraser, Paul E" sort="Fraser, Paul E" uniqKey="Fraser P" first="Paul E" last="Fraser">Paul E. Fraser</name><name sortKey="Iqbal, Sobia" sort="Iqbal, Sobia" uniqKey="Iqbal S" first="Sobia" last="Iqbal">Sobia Iqbal</name><name sortKey="Sri Renganathan, Sri Dushyaanthan" sort="Sri Renganathan, Sri Dushyaanthan" uniqKey="Sri Renganathan S" first="Sri Dushyaanthan" last="Sri Renganathan">Sri Dushyaanthan Sri Renganathan</name><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name></country><country name="États-Unis"><region name="Illinois"><name sortKey="Campbell, Edward M" sort="Campbell, Edward M" uniqKey="Campbell E" first="Edward M" last="Campbell">Edward M. Campbell</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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