Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.
Identifieur interne : 003733 ( PubMed/Corpus ); précédent : 003732; suivant : 003734Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.
Auteurs : Itamar Kass ; David E. Hoke ; Mauricio G S. Costa ; Cyril F. Reboul ; Benjamin T. Porebski ; Nathan P. Cowieson ; Hervé Leh ; Eugenia Pennacchietti ; Julia Mccoey ; Oded Kleifeld ; Carla Borri Voltattorni ; David Langley ; Brendan Roome ; Ian R. Mackay ; Daniel Christ ; David Perahia ; Malcolm Buckle ; Alessandro Paiardini ; Daniela De Biase ; Ashley M. BuckleSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2014.
English descriptors
- KwdEn :
- Autoantibodies (immunology), Autoimmunity, Diabetes Mellitus, Type 1 (immunology), Glutamate Decarboxylase (chemistry), Glutamate Decarboxylase (genetics), Glutamate Decarboxylase (immunology), Homeostasis (immunology), Humans, Molecular Dynamics Simulation, Neurotransmitter Agents (chemistry), Neurotransmitter Agents (genetics), Neurotransmitter Agents (immunology), Protein Multimerization, Structure-Activity Relationship, gamma-Aminobutyric Acid (chemistry), gamma-Aminobutyric Acid (genetics), gamma-Aminobutyric Acid (immunology).
- MESH :
- chemical , chemistry : Glutamate Decarboxylase, Neurotransmitter Agents, gamma-Aminobutyric Acid.
- chemical , genetics : Glutamate Decarboxylase, Neurotransmitter Agents, gamma-Aminobutyric Acid.
- chemical , immunology : Autoantibodies, Glutamate Decarboxylase, Neurotransmitter Agents, gamma-Aminobutyric Acid.
- immunology : Diabetes Mellitus, Type 1, Homeostasis.
- Autoimmunity, Humans, Molecular Dynamics Simulation, Protein Multimerization, Structure-Activity Relationship.
Abstract
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 (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo 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 apo 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 holo → apo 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 apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 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.
DOI: 10.1073/pnas.1403182111
PubMed: 24927554
Links to Exploration step
pubmed:24927554Le document en format XML
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Costa</name><affiliation><nlm:affiliation>Programa de Computação Científica, Fundação Oswaldo Cruz, 21949900 Rio de Janeiro, Brazil;</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology,Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3800, Australia;</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></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:affiliation>Australian Synchrotron, VIC 3168, Australia;</nlm:affiliation></affiliation></author><author><name sortKey="Leh, Herve" sort="Leh, Herve" uniqKey="Leh H" first="Hervé" last="Leh">Hervé Leh</name><affiliation><nlm:affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</nlm:affiliation></affiliation></author><author><name sortKey="Pennacchietti, Eugenia" sort="Pennacchietti, Eugenia" uniqKey="Pennacchietti E" first="Eugenia" last="Pennacchietti">Eugenia Pennacchietti</name><affiliation><nlm:affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, 04100 Latina, Italy;</nlm:affiliation></affiliation></author><author><name sortKey="Mccoey, Julia" sort="Mccoey, Julia" uniqKey="Mccoey J" first="Julia" last="Mccoey">Julia Mccoey</name><affiliation><nlm:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></affiliation></author><author><name sortKey="Kleifeld, Oded" sort="Kleifeld, Oded" uniqKey="Kleifeld O" first="Oded" last="Kleifeld">Oded Kleifeld</name><affiliation><nlm:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></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:affiliation>Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Verona, 37134 Verona, Italy;</nlm:affiliation></affiliation></author><author><name sortKey="Langley, David" sort="Langley, David" uniqKey="Langley D" first="David" last="Langley">David Langley</name><affiliation><nlm:affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</nlm:affiliation></affiliation></author><author><name sortKey="Roome, Brendan" sort="Roome, Brendan" uniqKey="Roome B" first="Brendan" last="Roome">Brendan Roome</name><affiliation><nlm:affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></affiliation></author><author><name sortKey="Christ, Daniel" sort="Christ, Daniel" uniqKey="Christ D" first="Daniel" last="Christ">Daniel Christ</name><affiliation><nlm:affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</nlm:affiliation></affiliation></author><author><name sortKey="Perahia, David" sort="Perahia, David" uniqKey="Perahia D" first="David" last="Perahia">David Perahia</name><affiliation><nlm:affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</nlm:affiliation></affiliation></author><author><name sortKey="Buckle, Malcolm" sort="Buckle, Malcolm" uniqKey="Buckle M" first="Malcolm" last="Buckle">Malcolm Buckle</name><affiliation><nlm:affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</nlm:affiliation></affiliation></author><author><name sortKey="Paiardini, Alessandro" sort="Paiardini, Alessandro" uniqKey="Paiardini A" first="Alessandro" last="Paiardini">Alessandro Paiardini</name><affiliation><nlm:affiliation>Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Sapienza Università di Roma, 00185 Rome, Italy.</nlm:affiliation></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:affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, 04100 Latina, Italy;</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology, ashley.buckle@monash.edu.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:24927554</idno><idno type="pmid">24927554</idno><idno type="doi">10.1073/pnas.1403182111</idno><idno type="wicri:Area/PubMed/Corpus">003733</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">003733</idno></publicationStmt><sourceDesc><biblStruct><analytic><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:affiliation>Department of Biochemistry and Molecular Biology,Victorian Life Sciences Computation Initiative Life Sciences Computation Centre, and.</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></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:affiliation>Programa de Computação Científica, Fundação Oswaldo Cruz, 21949900 Rio de Janeiro, Brazil;</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology,Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3800, Australia;</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></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:affiliation>Australian Synchrotron, VIC 3168, Australia;</nlm:affiliation></affiliation></author><author><name sortKey="Leh, Herve" sort="Leh, Herve" uniqKey="Leh H" first="Hervé" last="Leh">Hervé Leh</name><affiliation><nlm:affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</nlm:affiliation></affiliation></author><author><name sortKey="Pennacchietti, Eugenia" sort="Pennacchietti, Eugenia" uniqKey="Pennacchietti E" first="Eugenia" last="Pennacchietti">Eugenia Pennacchietti</name><affiliation><nlm:affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, 04100 Latina, Italy;</nlm:affiliation></affiliation></author><author><name sortKey="Mccoey, Julia" sort="Mccoey, Julia" uniqKey="Mccoey J" first="Julia" last="Mccoey">Julia Mccoey</name><affiliation><nlm:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></affiliation></author><author><name sortKey="Kleifeld, Oded" sort="Kleifeld, Oded" uniqKey="Kleifeld O" first="Oded" last="Kleifeld">Oded Kleifeld</name><affiliation><nlm:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></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:affiliation>Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Verona, 37134 Verona, Italy;</nlm:affiliation></affiliation></author><author><name sortKey="Langley, David" sort="Langley, David" uniqKey="Langley D" first="David" last="Langley">David Langley</name><affiliation><nlm:affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</nlm:affiliation></affiliation></author><author><name sortKey="Roome, Brendan" sort="Roome, Brendan" uniqKey="Roome B" first="Brendan" last="Roome">Brendan Roome</name><affiliation><nlm:affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology.</nlm:affiliation></affiliation></author><author><name sortKey="Christ, Daniel" sort="Christ, Daniel" uniqKey="Christ D" first="Daniel" last="Christ">Daniel Christ</name><affiliation><nlm:affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</nlm:affiliation></affiliation></author><author><name sortKey="Perahia, David" sort="Perahia, David" uniqKey="Perahia D" first="David" last="Perahia">David Perahia</name><affiliation><nlm:affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</nlm:affiliation></affiliation></author><author><name sortKey="Buckle, Malcolm" sort="Buckle, Malcolm" uniqKey="Buckle M" first="Malcolm" last="Buckle">Malcolm Buckle</name><affiliation><nlm:affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</nlm:affiliation></affiliation></author><author><name sortKey="Paiardini, Alessandro" sort="Paiardini, Alessandro" uniqKey="Paiardini A" first="Alessandro" last="Paiardini">Alessandro Paiardini</name><affiliation><nlm:affiliation>Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Sapienza Università di Roma, 00185 Rome, Italy.</nlm:affiliation></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:affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, 04100 Latina, Italy;</nlm:affiliation></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:affiliation>Department of Biochemistry and Molecular Biology, ashley.buckle@monash.edu.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Autoantibodies (immunology)</term><term>Autoimmunity</term><term>Diabetes Mellitus, Type 1 (immunology)</term><term>Glutamate Decarboxylase (chemistry)</term><term>Glutamate Decarboxylase (genetics)</term><term>Glutamate Decarboxylase (immunology)</term><term>Homeostasis (immunology)</term><term>Humans</term><term>Molecular Dynamics Simulation</term><term>Neurotransmitter Agents (chemistry)</term><term>Neurotransmitter Agents (genetics)</term><term>Neurotransmitter Agents (immunology)</term><term>Protein Multimerization</term><term>Structure-Activity Relationship</term><term>gamma-Aminobutyric Acid (chemistry)</term><term>gamma-Aminobutyric Acid (genetics)</term><term>gamma-Aminobutyric Acid (immunology)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Glutamate Decarboxylase</term><term>Neurotransmitter Agents</term><term>gamma-Aminobutyric Acid</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Glutamate Decarboxylase</term><term>Neurotransmitter Agents</term><term>gamma-Aminobutyric Acid</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Autoantibodies</term><term>Glutamate Decarboxylase</term><term>Neurotransmitter Agents</term><term>gamma-Aminobutyric Acid</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Diabetes Mellitus, Type 1</term><term>Homeostasis</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Autoimmunity</term><term>Humans</term><term>Molecular Dynamics Simulation</term><term>Protein Multimerization</term><term>Structure-Activity Relationship</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo 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 apo 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 holo → apo 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 apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">24927554</PMID><DateCreated><Year>2014</Year><Month>06</Month><Day>25</Day></DateCreated><DateCompleted><Year>2014</Year><Month>08</Month><Day>18</Day></DateCompleted><DateRevised><Year>2017</Year><Month>02</Month><Day>20</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1091-6490</ISSN><JournalIssue CitedMedium="Internet"><Volume>111</Volume><Issue>25</Issue><PubDate><Year>2014</Year><Month>Jun</Month><Day>24</Day></PubDate></JournalIssue><Title>Proceedings of the National Academy of Sciences of the United States of America</Title><ISOAbbreviation>Proc. Natl. Acad. Sci. U.S.A.</ISOAbbreviation></Journal><ArticleTitle>Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.</ArticleTitle><Pagination><MedlinePgn>E2524-9</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1403182111</ELocationID><Abstract><AbstractText>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 (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo 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 apo 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 holo → apo 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 apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kass</LastName><ForeName>Itamar</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology,Victorian Life Sciences Computation Initiative Life Sciences Computation Centre, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hoke</LastName><ForeName>David E</ForeName><Initials>DE</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Costa</LastName><ForeName>Mauricio G S</ForeName><Initials>MG</Initials><AffiliationInfo><Affiliation>Programa de Computação Científica, Fundação Oswaldo Cruz, 21949900 Rio de Janeiro, Brazil;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reboul</LastName><ForeName>Cyril F</ForeName><Initials>CF</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology,Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, VIC 3800, Australia;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Porebski</LastName><ForeName>Benjamin T</ForeName><Initials>BT</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cowieson</LastName><ForeName>Nathan P</ForeName><Initials>NP</Initials><AffiliationInfo><Affiliation>Australian Synchrotron, VIC 3168, Australia;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leh</LastName><ForeName>Hervé</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Pennacchietti</LastName><ForeName>Eugenia</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, 04100 Latina, Italy;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>McCoey</LastName><ForeName>Julia</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kleifeld</LastName><ForeName>Oded</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Borri Voltattorni</LastName><ForeName>Carla</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Dipartimento di Scienze della Vita e della Riproduzione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Verona, 37134 Verona, Italy;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Langley</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Roome</LastName><ForeName>Brendan</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mackay</LastName><ForeName>Ian R</ForeName><Initials>IR</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Christ</LastName><ForeName>Daniel</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Garvan Institute of Medical Research, Darlinghurst/Sydney, NSW 2010, Australia; and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Perahia</LastName><ForeName>David</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Buckle</LastName><ForeName>Malcolm</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure de Cachan, Centre National de la Recherche Scientifique, 61, F-94235 Cachan, France;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Paiardini</LastName><ForeName>Alessandro</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Sapienza Università di Roma, 00185 Rome, Italy.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>De Biase</LastName><ForeName>Daniela</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Università di Roma, 04100 Latina, Italy;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Buckle</LastName><ForeName>Ashley M</ForeName><Initials>AM</Initials><AffiliationInfo><Affiliation>Department of Biochemistry and Molecular Biology, ashley.buckle@monash.edu.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2014</Year><Month>06</Month><Day>09</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Proc Natl Acad Sci U S A</MedlineTA><NlmUniqueID>7505876</NlmUniqueID><ISSNLinking>0027-8424</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001323">Autoantibodies</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018377">Neurotransmitter Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>56-12-2</RegistryNumber><NameOfSubstance UI="D005680">gamma-Aminobutyric Acid</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 4.1.1.15</RegistryNumber><NameOfSubstance UI="D005968">Glutamate Decarboxylase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 4.1.1.15</RegistryNumber><NameOfSubstance UI="C401141">glutamate decarboxylase 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MajorTopicYN="N">Autoantibodies</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015551" MajorTopicYN="Y">Autoimmunity</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003922" MajorTopicYN="N">Diabetes Mellitus, Type 1</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005968" MajorTopicYN="Y">Glutamate Decarboxylase</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006706" MajorTopicYN="N">Homeostasis</DescriptorName><QualifierName UI="Q000276" MajorTopicYN="Y">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D056004" MajorTopicYN="Y">Molecular Dynamics Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018377" MajorTopicYN="Y">Neurotransmitter Agents</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055503" MajorTopicYN="N">Protein Multimerization</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005680" MajorTopicYN="Y">gamma-Aminobutyric Acid</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName></MeshHeading></MeshHeadingList><OtherID Source="NLM">PMC4078817</OtherID><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">GABA biosynthesis</Keyword><Keyword MajorTopicYN="N">autoepitopes</Keyword><Keyword MajorTopicYN="N">conformational dynamics</Keyword><Keyword MajorTopicYN="N">immunogenicity</Keyword><Keyword MajorTopicYN="N">normal mode analysis</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2014</Year><Month>6</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2014</Year><Month>6</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2014</Year><Month>8</Month><Day>19</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">24927554</ArticleId><ArticleId 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