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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis</title><author><name sortKey="Kass, Itamar" sort="Kass, Itamar" uniqKey="Kass I" first="Itamar" last="Kass">Itamar Kass</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff2">Victorian Life Sciences Computation Initiative Life Sciences Computation Centre</nlm:aff></affiliation></author><author><name sortKey="Hoke, David E" sort="Hoke, David E" uniqKey="Hoke D" first="David E." last="Hoke">David E. Hoke</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Costa, Mauricio G S" sort="Costa, Mauricio G S" uniqKey="Costa M" first="Mauricio G. S." last="Costa">Mauricio G. S. Costa</name><affiliation><nlm:aff id="aff4">Programa de Computação Científica,<institution>Fundação Oswaldo Cruz</institution>, 21949900 Rio de Janeiro,<country>Brazil</country>;</nlm:aff></affiliation></author><author><name sortKey="Reboul, Cyril F" sort="Reboul, Cyril F" uniqKey="Reboul C" first="Cyril F." last="Reboul">Cyril F. Reboul</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics,<institution>Monash University</institution>, Clayton, VIC 3800,<country>Australia</country>;</nlm:aff></affiliation></author><author><name sortKey="Porebski, Benjamin T" sort="Porebski, Benjamin T" uniqKey="Porebski B" first="Benjamin T." last="Porebski">Benjamin T. Porebski</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Cowieson, Nathan P" sort="Cowieson, Nathan P" uniqKey="Cowieson N" first="Nathan P." last="Cowieson">Nathan P. Cowieson</name><affiliation><nlm:aff id="aff5"><institution>Australian Synchrotron</institution>, VIC 3168,<country>Australia</country>;</nlm:aff></affiliation></author><author><name sortKey="Leh, Herve" sort="Leh, Herve" uniqKey="Leh H" first="Hervé" last="Leh">Hervé Leh</name><affiliation><nlm:aff id="aff6">Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan,<institution>Centre National de la Recherche Scientifique</institution>, 61, F-94235 Cachan,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Pennacchietti, Eugenia" sort="Pennacchietti, Eugenia" uniqKey="Pennacchietti E" first="Eugenia" last="Pennacchietti">Eugenia Pennacchietti</name><affiliation><nlm:aff id="aff7">Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche,<institution>Sapienza Università di Roma</institution>, 04100 Latina,<country>Italy</country>;</nlm:aff></affiliation></author><author><name sortKey="Mccoey, Julia" sort="Mccoey, Julia" uniqKey="Mccoey J" first="Julia" last="Mccoey">Julia Mccoey</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Kleifeld, Oded" sort="Kleifeld, Oded" uniqKey="Kleifeld O" first="Oded" last="Kleifeld">Oded Kleifeld</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Borri Voltattorni, Carla" sort="Borri Voltattorni, Carla" uniqKey="Borri Voltattorni C" first="Carla" last="Borri Voltattorni">Carla Borri Voltattorni</name><affiliation><nlm:aff id="aff8">Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia,<institution>Università degli Studi di Verona</institution>, 37134 Verona,<country>Italy</country>;</nlm:aff></affiliation></author><author><name sortKey="Langley, David" sort="Langley, David" uniqKey="Langley D" first="David" last="Langley">David Langley</name><affiliation><nlm:aff wicri:cut="; and" id="aff9"><institution>Garvan Institute of Medical Research</institution>, Darlinghurst/Sydney, NSW 2010,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Roome, Brendan" sort="Roome, Brendan" uniqKey="Roome B" first="Brendan" last="Roome">Brendan Roome</name><affiliation><nlm:aff wicri:cut="; and" id="aff9"><institution>Garvan Institute of Medical Research</institution>, Darlinghurst/Sydney, NSW 2010,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Mackay, Ian R" sort="Mackay, Ian R" uniqKey="Mackay I" first="Ian R." last="Mackay">Ian R. Mackay</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Christ, Daniel" sort="Christ, Daniel" uniqKey="Christ D" first="Daniel" last="Christ">Daniel Christ</name><affiliation><nlm:aff wicri:cut="; and" id="aff9"><institution>Garvan Institute of Medical Research</institution>, Darlinghurst/Sydney, NSW 2010,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Perahia, David" sort="Perahia, David" uniqKey="Perahia D" first="David" last="Perahia">David Perahia</name><affiliation><nlm:aff id="aff6">Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan,<institution>Centre National de la Recherche Scientifique</institution>, 61, F-94235 Cachan,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Buckle, Malcolm" sort="Buckle, Malcolm" uniqKey="Buckle M" first="Malcolm" last="Buckle">Malcolm Buckle</name><affiliation><nlm:aff id="aff6">Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan,<institution>Centre National de la Recherche Scientifique</institution>, 61, F-94235 Cachan,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Paiardini, Alessandro" sort="Paiardini, Alessandro" uniqKey="Paiardini A" first="Alessandro" last="Paiardini">Alessandro Paiardini</name><affiliation><nlm:aff id="aff10">Dipartimento di Scienze Biochimiche “A. Rossi Fanelli,”<institution>Sapienza Università di Roma</institution>, 00185 Rome,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="De Biase, Daniela" sort="De Biase, Daniela" uniqKey="De Biase D" first="Daniela" last="De Biase">Daniela De Biase</name><affiliation><nlm:aff id="aff7">Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche,<institution>Sapienza Università di Roma</institution>, 04100 Latina,<country>Italy</country>;</nlm:aff></affiliation></author><author><name sortKey="Buckle, Ashley M" sort="Buckle, Ashley M" uniqKey="Buckle A" first="Ashley M." last="Buckle">Ashley M. Buckle</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">24927554</idno><idno type="pmc">4078817</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078817</idno><idno type="RBID">PMC:4078817</idno><idno type="doi">10.1073/pnas.1403182111</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">001B97</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001B97</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis</title><author><name sortKey="Kass, Itamar" sort="Kass, Itamar" uniqKey="Kass I" first="Itamar" last="Kass">Itamar Kass</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff2">Victorian Life Sciences Computation Initiative Life Sciences Computation Centre</nlm:aff></affiliation></author><author><name sortKey="Hoke, David E" sort="Hoke, David E" uniqKey="Hoke D" first="David E." last="Hoke">David E. Hoke</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Costa, Mauricio G S" sort="Costa, Mauricio G S" uniqKey="Costa M" first="Mauricio G. S." last="Costa">Mauricio G. S. Costa</name><affiliation><nlm:aff id="aff4">Programa de Computação Científica,<institution>Fundação Oswaldo Cruz</institution>, 21949900 Rio de Janeiro,<country>Brazil</country>;</nlm:aff></affiliation></author><author><name sortKey="Reboul, Cyril F" sort="Reboul, Cyril F" uniqKey="Reboul C" first="Cyril F." last="Reboul">Cyril F. Reboul</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics,<institution>Monash University</institution>, Clayton, VIC 3800,<country>Australia</country>;</nlm:aff></affiliation></author><author><name sortKey="Porebski, Benjamin T" sort="Porebski, Benjamin T" uniqKey="Porebski B" first="Benjamin T." last="Porebski">Benjamin T. Porebski</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Cowieson, Nathan P" sort="Cowieson, Nathan P" uniqKey="Cowieson N" first="Nathan P." last="Cowieson">Nathan P. Cowieson</name><affiliation><nlm:aff id="aff5"><institution>Australian Synchrotron</institution>, VIC 3168,<country>Australia</country>;</nlm:aff></affiliation></author><author><name sortKey="Leh, Herve" sort="Leh, Herve" uniqKey="Leh H" first="Hervé" last="Leh">Hervé Leh</name><affiliation><nlm:aff id="aff6">Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan,<institution>Centre National de la Recherche Scientifique</institution>, 61, F-94235 Cachan,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Pennacchietti, Eugenia" sort="Pennacchietti, Eugenia" uniqKey="Pennacchietti E" first="Eugenia" last="Pennacchietti">Eugenia Pennacchietti</name><affiliation><nlm:aff id="aff7">Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche,<institution>Sapienza Università di Roma</institution>, 04100 Latina,<country>Italy</country>;</nlm:aff></affiliation></author><author><name sortKey="Mccoey, Julia" sort="Mccoey, Julia" uniqKey="Mccoey J" first="Julia" last="Mccoey">Julia Mccoey</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Kleifeld, Oded" sort="Kleifeld, Oded" uniqKey="Kleifeld O" first="Oded" last="Kleifeld">Oded Kleifeld</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Borri Voltattorni, Carla" sort="Borri Voltattorni, Carla" uniqKey="Borri Voltattorni C" first="Carla" last="Borri Voltattorni">Carla Borri Voltattorni</name><affiliation><nlm:aff id="aff8">Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia,<institution>Università degli Studi di Verona</institution>, 37134 Verona,<country>Italy</country>;</nlm:aff></affiliation></author><author><name sortKey="Langley, David" sort="Langley, David" uniqKey="Langley D" first="David" last="Langley">David Langley</name><affiliation><nlm:aff wicri:cut="; and" id="aff9"><institution>Garvan Institute of Medical Research</institution>, Darlinghurst/Sydney, NSW 2010,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Roome, Brendan" sort="Roome, Brendan" uniqKey="Roome B" first="Brendan" last="Roome">Brendan Roome</name><affiliation><nlm:aff wicri:cut="; and" id="aff9"><institution>Garvan Institute of Medical Research</institution>, Darlinghurst/Sydney, NSW 2010,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Mackay, Ian R" sort="Mackay, Ian R" uniqKey="Mackay I" first="Ian R." last="Mackay">Ian R. Mackay</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author><author><name sortKey="Christ, Daniel" sort="Christ, Daniel" uniqKey="Christ D" first="Daniel" last="Christ">Daniel Christ</name><affiliation><nlm:aff wicri:cut="; and" id="aff9"><institution>Garvan Institute of Medical Research</institution>, Darlinghurst/Sydney, NSW 2010,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Perahia, David" sort="Perahia, David" uniqKey="Perahia D" first="David" last="Perahia">David Perahia</name><affiliation><nlm:aff id="aff6">Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan,<institution>Centre National de la Recherche Scientifique</institution>, 61, F-94235 Cachan,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Buckle, Malcolm" sort="Buckle, Malcolm" uniqKey="Buckle M" first="Malcolm" last="Buckle">Malcolm Buckle</name><affiliation><nlm:aff id="aff6">Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan,<institution>Centre National de la Recherche Scientifique</institution>, 61, F-94235 Cachan,<country>France</country>;</nlm:aff></affiliation></author><author><name sortKey="Paiardini, Alessandro" sort="Paiardini, Alessandro" uniqKey="Paiardini A" first="Alessandro" last="Paiardini">Alessandro Paiardini</name><affiliation><nlm:aff id="aff10">Dipartimento di Scienze Biochimiche “A. Rossi Fanelli,”<institution>Sapienza Università di Roma</institution>, 00185 Rome,<country>Italy</country></nlm:aff></affiliation></author><author><name sortKey="De Biase, Daniela" sort="De Biase, Daniela" uniqKey="De Biase D" first="Daniela" last="De Biase">Daniela De Biase</name><affiliation><nlm:aff id="aff7">Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche,<institution>Sapienza Università di Roma</institution>, 04100 Latina,<country>Italy</country>;</nlm:aff></affiliation></author><author><name sortKey="Buckle, Ashley M" sort="Buckle, Ashley M" uniqKey="Buckle A" first="Ashley M." last="Buckle">Ashley M. Buckle</name><affiliation><nlm:aff id="aff1">Department of Biochemistry and Molecular Biology,</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Autoimmune type 1 diabetes is characterized by the formation of self-reactive antibodies. A prevalent human autoantigen is glutamate decarboxylase (GAD)65, a highly predictive marker that can precede the emergence of disease by up to several years. Intriguingly, the closely related isoform GAD67 is not immunogenic. What are the determinants of the unique self-reactivity of GAD65 vs. GAD67? We show that, unlike GAD67, GAD65 is highly flexible and exists in multiple structural forms. We show that self-antibodies bind differentially to these GAD65 forms. These properties may be an undesirable consequence of conformational flexibility necessary for enzyme function. Our findings, thus, provide insights into how structural flexibility governs protein immunogenicity in autoimmune diabetes and have implications for therapeutic antibody and vaccine design.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">24927554</article-id><article-id pub-id-type="pmc">4078817</article-id><article-id pub-id-type="publisher-id">201403182</article-id><article-id pub-id-type="doi">10.1073/pnas.1403182111</article-id><article-categories><subj-group subj-group-type="heading"><subject>PNAS Plus</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Biophysics and Computational Biology</subject></subj-group></subj-group><series-title>PNAS Plus</series-title></article-categories><title-group><article-title>Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis</article-title><alt-title alt-title-type="short">Cofactor control of GAD65 dynamics</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Kass</surname><given-names>Itamar</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hoke</surname><given-names>David E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Costa</surname><given-names>Mauricio G. S.</given-names></name><xref ref-type="aff" rid="aff4"><sup>c</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reboul</surname><given-names>Cyril F.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Porebski</surname><given-names>Benjamin T.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cowieson</surname><given-names>Nathan P.</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Leh</surname><given-names>Hervé</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pennacchietti</surname><given-names>Eugenia</given-names></name><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>McCoey</surname><given-names>Julia</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kleifeld</surname><given-names>Oded</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Borri Voltattorni</surname><given-names>Carla</given-names></name><xref ref-type="aff" rid="aff8"><sup>h</sup></xref></contrib><contrib contrib-type="author"><name><surname>Langley</surname><given-names>David</given-names></name><xref ref-type="aff" rid="aff9"><sup>i</sup></xref></contrib><contrib contrib-type="author"><name><surname>Roome</surname><given-names>Brendan</given-names></name><xref ref-type="aff" rid="aff9"><sup>i</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mackay</surname><given-names>Ian R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Christ</surname><given-names>Daniel</given-names></name><xref ref-type="aff" rid="aff9"><sup>i</sup></xref></contrib><contrib contrib-type="author"><name><surname>Perahia</surname><given-names>David</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buckle</surname><given-names>Malcolm</given-names></name><xref ref-type="aff" rid="aff6"><sup>f</sup></xref></contrib><contrib contrib-type="author"><name><surname>Paiardini</surname><given-names>Alessandro</given-names></name><xref ref-type="aff" rid="aff10"><sup>j</sup></xref></contrib><contrib contrib-type="author"><name><surname>De Biase</surname><given-names>Daniela</given-names></name><xref ref-type="aff" rid="aff7"><sup>g</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buckle</surname><given-names>Ashley M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1"><sup>a</sup>Department of Biochemistry and Molecular Biology,</aff><aff id="aff2"><sup>b</sup>Victorian Life Sciences Computation Initiative Life Sciences Computation Centre, and</aff><aff id="aff3"><sup>d</sup>Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics,<institution>Monash University</institution>, Clayton, VIC 3800,<country>Australia</country>;</aff><aff id="aff4"><sup>c</sup>Programa de Computação Científica,<institution>Fundação Oswaldo Cruz</institution>, 21949900 Rio de Janeiro,<country>Brazil</country>;</aff><aff id="aff5"><sup>e</sup><institution>Australian Synchrotron</institution>, VIC 3168,<country>Australia</country>;</aff><aff id="aff6"><sup>f</sup>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan,<institution>Centre National de la Recherche Scientifique</institution>, 61, F-94235 Cachan,<country>France</country>;</aff><aff id="aff7"><sup>g</sup>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche,<institution>Sapienza Università di Roma</institution>, 04100 Latina,<country>Italy</country>;</aff><aff id="aff8"><sup>h</sup>Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia,<institution>Università degli Studi di Verona</institution>, 37134 Verona,<country>Italy</country>;</aff><aff id="aff9"><sup>i</sup><institution>Garvan Institute of Medical Research</institution>, Darlinghurst/Sydney, NSW 2010,<country>Australia</country>; and</aff><aff id="aff10"><sup>j</sup>Dipartimento di Scienze Biochimiche “A. Rossi Fanelli,”<institution>Sapienza Università di Roma</institution>, 00185 Rome,<country>Italy</country></aff></contrib-group><author-notes><corresp id="cor1"><sup>2</sup>To whom correspondence should be addressed. E-mail: <email>ashley.buckle@monash.edu</email>.</corresp><fn fn-type="edited-by"><p>Edited by Benoit Roux, University of Chicago, Chicago, IL, and accepted by the Editorial Board April 22, 2014 (received for review February 22, 2014)</p></fn><fn fn-type="con"><p>Author contributions: I.K., D.E.H., M.G.S.C., and A.M.B. designed research; I.K., D.E.H., M.G.S.C., C.F.R., N.P.C., H.L., E.P., D.P., M.B., A.P., and D.D.B. performed research; B.T.P., J.M., O.K., C.B.V., D.L., B.R., and D.C. contributed new reagents/analytic tools; I.K., D.E.H., M.G.S.C., N.P.C., J.M., D.C., D.P., M.B., A.P., D.D.B., and A.M.B. analyzed data; and I.K., D.E.H., M.G.S.C., I.R.M., M.B., D.D.B., and A.M.B. wrote the paper.</p></fn><fn fn-type="equal" id="fn1"><p><sup>1</sup>I.K., D.E.H., and M.G.S.C. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>24</day><month>6</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>9</day><month>6</month><year>2014</year></pub-date><volume>111</volume><issue>25</issue><fpage>E2524</fpage><lpage>E2529</lpage><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="pnas.201403182.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Autoimmune type 1 diabetes is characterized by the formation of self-reactive antibodies. A prevalent human autoantigen is glutamate decarboxylase (GAD)65, a highly predictive marker that can precede the emergence of disease by up to several years. Intriguingly, the closely related isoform GAD67 is not immunogenic. What are the determinants of the unique self-reactivity of GAD65 vs. GAD67? We show that, unlike GAD67, GAD65 is highly flexible and exists in multiple structural forms. We show that self-antibodies bind differentially to these GAD65 forms. These properties may be an undesirable consequence of conformational flexibility necessary for enzyme function. Our findings, thus, provide insights into how structural flexibility governs protein immunogenicity in autoimmune diabetes and have implications for therapeutic antibody and vaccine design.</p></abstract><abstract><p>The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5′-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (<italic>holo</italic>GAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive <italic>apo</italic> form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the <italic>apo</italic> form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the <italic>holo</italic> → <italic>apo</italic> conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5′-phosphate–binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with <italic>apo</italic>GAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of <italic>apo</italic>GAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies.</p></abstract><kwd-group><kwd>conformational dynamics</kwd><kwd>normal mode analysis</kwd><kwd>GABA biosynthesis</kwd><kwd>immunogenicity</kwd><kwd>autoepitopes</kwd></kwd-group><counts><page-count count="6"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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