AustralieFrV1, Ncbi, Checkpoint, bibRecord, 001B19

Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis

Identifieur interne : 001B19 ( Ncbi/Checkpoint ); précédent : 001B18; suivant : 001B20

Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis

Auteurs : Itamar Kass ; David E. Hoke ; Mauricio G. S. Costa [Brésil] ; Cyril F. Reboul [Australie] ; Benjamin T. Porebski ; Nathan P. Cowieson [Australie] ; Hervé Leh [France] ; Eugenia Pennacchietti [Italie] ; Julia Mccoey ; Oded Kleifeld ; Carla Borri Voltattorni [Italie] ; David Langley [Australie] ; Brendan Roome [Australie] ; Ian R. Mackay ; Daniel Christ [Australie] ; David Perahia [France] ; Malcolm Buckle [France] ; Alessandro Paiardini [Italie] ; Daniela De Biase [Italie] ; Ashley M. Buckle

Source :

Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2014.

RBID : PMC:4078817

Descripteurs français

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

Significance

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078817

DOI: 10.1073/pnas.1403182111
PubMed: 24927554
PubMed Central: 4078817

Affiliations:

Australie, Brésil, France, Italie

Links to Exploration step

PMC:4078817

Le document en format XML

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, 04100 Latina,<country>Italy</country>
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</affiliation>
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<author><name sortKey="Christ, Daniel" sort="Christ, Daniel" uniqKey="Christ D" first="Daniel" last="Christ">Daniel Christ</name>
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, 61, F-94235 Cachan,<country>France</country>
;</nlm:aff>
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, 61, F-94235 Cachan,<country>France</country>
;</nlm:aff>
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, 00185 Rome,<country>Italy</country>
</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author><name sortKey="De Biase, Daniela" sort="De Biase, Daniela" uniqKey="De Biase D" first="Daniela" last="De Biase">Daniela De Biase</name>
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, 04100 Latina,<country>Italy</country>
;</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<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>
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<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>
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<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="KwdFr" xml:lang="fr"><term>Acide gamma-amino-butyrique ()</term>
<term>Acide gamma-amino-butyrique (génétique)</term>
<term>Acide gamma-amino-butyrique (immunologie)</term>
<term>Agents neuromédiateurs ()</term>
<term>Agents neuromédiateurs (génétique)</term>
<term>Agents neuromédiateurs (immunologie)</term>
<term>Auto-immunité</term>
<term>Autoanticorps (immunologie)</term>
<term>Diabète de type 1 (immunologie)</term>
<term>Glutamate decarboxylase ()</term>
<term>Glutamate decarboxylase (génétique)</term>
<term>Glutamate decarboxylase (immunologie)</term>
<term>Homéostasie (immunologie)</term>
<term>Humains</term>
<term>Multimérisation de protéines</term>
<term>Relation structure-activité</term>
<term>Simulation de dynamique moléculaire</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="génétique" xml:lang="fr"><term>Acide gamma-amino-butyrique</term>
<term>Agents neuromédiateurs</term>
<term>Glutamate decarboxylase</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Acide gamma-amino-butyrique</term>
<term>Agents neuromédiateurs</term>
<term>Autoanticorps</term>
<term>Diabète de type 1</term>
<term>Glutamate decarboxylase</term>
<term>Homéostasie</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>
<keywords scheme="MESH" xml:lang="fr"><term>Acide gamma-amino-butyrique</term>
<term>Agents neuromédiateurs</term>
<term>Auto-immunité</term>
<term>Glutamate decarboxylase</term>
<term>Humains</term>
<term>Multimérisation de protéines</term>
<term>Relation structure-activité</term>
<term>Simulation de dynamique moléculaire</term>
</keywords>
</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>
<affiliations><list><country><li>Australie</li>
<li>Brésil</li>
<li>France</li>
<li>Italie</li>
</country>
</list>
<tree><noCountry><name sortKey="Buckle, Ashley M" sort="Buckle, Ashley M" uniqKey="Buckle A" first="Ashley M." last="Buckle">Ashley M. Buckle</name>
<name sortKey="Hoke, David E" sort="Hoke, David E" uniqKey="Hoke D" first="David E." last="Hoke">David E. Hoke</name>
<name sortKey="Kass, Itamar" sort="Kass, Itamar" uniqKey="Kass I" first="Itamar" last="Kass">Itamar Kass</name>
<name sortKey="Kleifeld, Oded" sort="Kleifeld, Oded" uniqKey="Kleifeld O" first="Oded" last="Kleifeld">Oded Kleifeld</name>
<name sortKey="Mackay, Ian R" sort="Mackay, Ian R" uniqKey="Mackay I" first="Ian R." last="Mackay">Ian R. Mackay</name>
<name sortKey="Mccoey, Julia" sort="Mccoey, Julia" uniqKey="Mccoey J" first="Julia" last="Mccoey">Julia Mccoey</name>
<name sortKey="Porebski, Benjamin T" sort="Porebski, Benjamin T" uniqKey="Porebski B" first="Benjamin T." last="Porebski">Benjamin T. Porebski</name>
</noCountry>
<country name="Brésil"><noRegion><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>
</noRegion>
</country>
<country name="Australie"><noRegion><name sortKey="Reboul, Cyril F" sort="Reboul, Cyril F" uniqKey="Reboul C" first="Cyril F." last="Reboul">Cyril F. Reboul</name>
</noRegion>
<name sortKey="Christ, Daniel" sort="Christ, Daniel" uniqKey="Christ D" first="Daniel" last="Christ">Daniel Christ</name>
<name sortKey="Cowieson, Nathan P" sort="Cowieson, Nathan P" uniqKey="Cowieson N" first="Nathan P." last="Cowieson">Nathan P. Cowieson</name>
<name sortKey="Langley, David" sort="Langley, David" uniqKey="Langley D" first="David" last="Langley">David Langley</name>
<name sortKey="Roome, Brendan" sort="Roome, Brendan" uniqKey="Roome B" first="Brendan" last="Roome">Brendan Roome</name>
</country>
<country name="France"><noRegion><name sortKey="Leh, Herve" sort="Leh, Herve" uniqKey="Leh H" first="Hervé" last="Leh">Hervé Leh</name>
</noRegion>
<name sortKey="Buckle, Malcolm" sort="Buckle, Malcolm" uniqKey="Buckle M" first="Malcolm" last="Buckle">Malcolm Buckle</name>
<name sortKey="Perahia, David" sort="Perahia, David" uniqKey="Perahia D" first="David" last="Perahia">David Perahia</name>
</country>
<country name="Italie"><noRegion><name sortKey="Pennacchietti, Eugenia" sort="Pennacchietti, Eugenia" uniqKey="Pennacchietti E" first="Eugenia" last="Pennacchietti">Eugenia Pennacchietti</name>
</noRegion>
<name sortKey="Borri Voltattorni, Carla" sort="Borri Voltattorni, Carla" uniqKey="Borri Voltattorni C" first="Carla" last="Borri Voltattorni">Carla Borri Voltattorni</name>
<name sortKey="De Biase, Daniela" sort="De Biase, Daniela" uniqKey="De Biase D" first="Daniela" last="De Biase">Daniela De Biase</name>
<name sortKey="Paiardini, Alessandro" sort="Paiardini, Alessandro" uniqKey="Paiardini A" first="Alessandro" last="Paiardini">Alessandro Paiardini</name>
</country>
</tree>
</affiliations>
</record>

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Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis

Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis

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