The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers*
Identifieur interne : 000483 ( Main/Merge ); précédent : 000482; suivant : 000484The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers*
Auteurs : Cristiane Latge ; Katia M. S. Cabral ; Guilherme A. P. De Oliveira ; Diana P. Raymundo ; Julia A. Freitas ; Laizes Johanson ; Luciana F. Romão ; Fernando L. Palhano ; Torsten Herrmann ; Marcius S. Almeida ; Debora FoguelSource :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2015.
English descriptors
- KwdEn :
- Animals, Biopolymers (metabolism), Cell Line, Crystallography, X-Ray, Humans, Mice, Nerve Growth Factors (chemistry), Nerve Growth Factors (physiology), Neuroprotective Agents, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Structure-Activity Relationship, alpha-Synuclein (metabolism).
- MESH :
- chemical , chemistry : Nerve Growth Factors.
- chemical , metabolism : Biopolymers, alpha-Synuclein.
- chemical , physiology : Nerve Growth Factors.
- Animals, Cell Line, Crystallography, X-Ray, Humans, Mice, Neuroprotective Agents, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Structure-Activity Relationship.
- mix :
Abstract
Url:
DOI: 10.1074/jbc.M115.662254
PubMed: 26149686
PubMed Central: 4536457
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PMC:4536457Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers<xref ref-type="fn" rid="FN1">*</xref>
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<author><name sortKey="Almeida, Marcius S" sort="Almeida, Marcius S" uniqKey="Almeida M" first="Marcius S." last="Almeida">Marcius S. Almeida</name>
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<series><title level="j">The Journal of Biological Chemistry</title>
<idno type="ISSN">0021-9258</idno>
<idno type="eISSN">1083-351X</idno>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Biopolymers (metabolism)</term>
<term>Cell Line</term>
<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Mice</term>
<term>Nerve Growth Factors (chemistry)</term>
<term>Nerve Growth Factors (physiology)</term>
<term>Neuroprotective Agents</term>
<term>Nuclear Magnetic Resonance, Biomolecular</term>
<term>Protein Conformation</term>
<term>Structure-Activity Relationship</term>
<term>alpha-Synuclein (metabolism)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Nerve Growth Factors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Biopolymers</term>
<term>alpha-Synuclein</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Nerve Growth Factors</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Mice</term>
<term>Neuroprotective Agents</term>
<term>Nuclear Magnetic Resonance, Biomolecular</term>
<term>Protein Conformation</term>
<term>Structure-Activity Relationship</term>
</keywords>
<keywords scheme="mix" xml:lang="en"><term>Parkinson disease</term>
<term>neurodegeneration</term>
<term>neurotrophic factor</term>
<term>protein dynamic</term>
<term>protein structure</term>
<term>α-synuclein (a-synuclein)</term>
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<front><div type="abstract" xml:lang="en"><p><bold>Background:</bold>
Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent for treating Parkinson disease.</p>
<p><bold>Results:</bold>
We determined the solution structure of CDNF and demonstrated its neuroprotective effects against insults caused by α-synuclein oligomers.</p>
<p><bold>Conclusion:</bold>
We identified structural features of CDNF that might correspond with its physiological activity.</p>
<p><bold>Significance:</bold>
This work strengthens the therapeutic relevance of using CDNF to treat neurodegenerative diseases.</p>
</div>
</front>
</TEI>
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<front><div type="abstract" xml:lang="en">Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent for Parkinson disease. As such, there has been great interest in studying its mode of action, which remains unknown. The three-dimensional crystal structure of the N terminus (residues 9-107) of CDNF has been determined, but there have been no published structural studies on the full-length protein due to proteolysis of its C-terminal domain, which is considered intrinsically disordered. An improved purification protocol enabled us to obtain active full-length CDNF and to determine its three-dimensional structure in solution. CDNF contains two well folded domains (residues 10-100 and 111-157) that are linked by a loop of intermediate flexibility. We identified two surface patches on the N-terminal domain that were characterized by increased conformational dynamics that should allow them to embrace active sites. One of these patches is formed by residues Ser-33, Leu-34, Ala-66, Lys-68, Ile-69, Leu-70, Ser-71, and Glu-72. The other includes a flexibly disordered N-terminal tail (residues 1-9), followed by the N-terminal portion of α-helix 1 (residues Cys-11, Glu-12, Val-13, Lys-15, and Glu-16) and residue Glu-88. The surface of the C-terminal domain contains two conserved active sites, which have previously been identified in mesencephalic astrocyte-derived neurotrophic factor, a CDNF paralog, which corresponds to its intracellular mode of action. We also showed that CDNF was able to protect dopaminergic neurons against injury caused by α-synuclein oligomers. This advises its use against physiological damages caused by α-synuclein oligomers, as observed in Parkinson disease and several other neurodegenerative diseases.</div>
</front>
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<PMC><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers<xref ref-type="fn" rid="FN1">*</xref>
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<author><name sortKey="Latge, Cristiane" sort="Latge, Cristiane" uniqKey="Latge C" first="Cristiane" last="Latge">Cristiane Latge</name>
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<author><name sortKey="Cabral, Katia M S" sort="Cabral, Katia M S" uniqKey="Cabral K" first="Katia M. S." last="Cabral">Katia M. S. Cabral</name>
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<author><name sortKey="De Oliveira, Guilherme A P" sort="De Oliveira, Guilherme A P" uniqKey="De Oliveira G" first="Guilherme A. P." last="De Oliveira">Guilherme A. P. De Oliveira</name>
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</affiliation>
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<author><name sortKey="Raymundo, Diana P" sort="Raymundo, Diana P" uniqKey="Raymundo D" first="Diana P." last="Raymundo">Diana P. Raymundo</name>
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<author><name sortKey="Freitas, Julia A" sort="Freitas, Julia A" uniqKey="Freitas J" first="Julia A." last="Freitas">Julia A. Freitas</name>
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<author><name sortKey="Johanson, Laizes" sort="Johanson, Laizes" uniqKey="Johanson L" first="Laizes" last="Johanson">Laizes Johanson</name>
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</affiliation>
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<author><name sortKey="Romao, Luciana F" sort="Romao, Luciana F" uniqKey="Romao L" first="Luciana F." last="Romão">Luciana F. Romão</name>
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<author><name sortKey="Palhano, Fernando L" sort="Palhano, Fernando L" uniqKey="Palhano F" first="Fernando L." last="Palhano">Fernando L. Palhano</name>
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<author><name sortKey="Herrmann, Torsten" sort="Herrmann, Torsten" uniqKey="Herrmann T" first="Torsten" last="Herrmann">Torsten Herrmann</name>
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</affiliation>
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<author><name sortKey="Almeida, Marcius S" sort="Almeida, Marcius S" uniqKey="Almeida M" first="Marcius S." last="Almeida">Marcius S. Almeida</name>
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<affiliation><nlm:aff id="aff4"></nlm:aff>
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<author><name sortKey="Foguel, Debora" sort="Foguel, Debora" uniqKey="Foguel D" first="Debora" last="Foguel">Debora Foguel</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Solution Structure and Dynamics of Full-length Human Cerebral Dopamine Neurotrophic Factor and Its Neuroprotective Role against α-Synuclein Oligomers<xref ref-type="fn" rid="FN1">*</xref>
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<author><name sortKey="Latge, Cristiane" sort="Latge, Cristiane" uniqKey="Latge C" first="Cristiane" last="Latge">Cristiane Latge</name>
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<author><name sortKey="Cabral, Katia M S" sort="Cabral, Katia M S" uniqKey="Cabral K" first="Katia M. S." last="Cabral">Katia M. S. Cabral</name>
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<author><name sortKey="De Oliveira, Guilherme A P" sort="De Oliveira, Guilherme A P" uniqKey="De Oliveira G" first="Guilherme A. P." last="De Oliveira">Guilherme A. P. De Oliveira</name>
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<author><name sortKey="Johanson, Laizes" sort="Johanson, Laizes" uniqKey="Johanson L" first="Laizes" last="Johanson">Laizes Johanson</name>
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<author><name sortKey="Palhano, Fernando L" sort="Palhano, Fernando L" uniqKey="Palhano F" first="Fernando L." last="Palhano">Fernando L. Palhano</name>
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<author><name sortKey="Herrmann, Torsten" sort="Herrmann, Torsten" uniqKey="Herrmann T" first="Torsten" last="Herrmann">Torsten Herrmann</name>
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<author><name sortKey="Almeida, Marcius S" sort="Almeida, Marcius S" uniqKey="Almeida M" first="Marcius S." last="Almeida">Marcius S. Almeida</name>
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<affiliation><nlm:aff id="aff4"></nlm:aff>
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<author><name sortKey="Foguel, Debora" sort="Foguel, Debora" uniqKey="Foguel D" first="Debora" last="Foguel">Debora Foguel</name>
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<series><title level="j">The Journal of Biological Chemistry</title>
<idno type="ISSN">0021-9258</idno>
<idno type="eISSN">1083-351X</idno>
<imprint><date when="2015">2015</date>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Biopolymers (metabolism)</term>
<term>Cell Line</term>
<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Mice</term>
<term>Nerve Growth Factors (chemistry)</term>
<term>Nerve Growth Factors (physiology)</term>
<term>Neuroprotective Agents</term>
<term>Nuclear Magnetic Resonance, Biomolecular</term>
<term>Protein Conformation</term>
<term>Structure-Activity Relationship</term>
<term>alpha-Synuclein (metabolism)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Nerve Growth Factors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Biopolymers</term>
<term>alpha-Synuclein</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Nerve Growth Factors</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Mice</term>
<term>Neuroprotective Agents</term>
<term>Nuclear Magnetic Resonance, Biomolecular</term>
<term>Protein Conformation</term>
<term>Structure-Activity Relationship</term>
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<front><div type="abstract" xml:lang="en"><p><bold>Background:</bold>
Cerebral dopamine neurotrophic factor (CDNF) is a promising therapeutic agent for treating Parkinson disease.</p>
<p><bold>Results:</bold>
We determined the solution structure of CDNF and demonstrated its neuroprotective effects against insults caused by α-synuclein oligomers.</p>
<p><bold>Conclusion:</bold>
We identified structural features of CDNF that might correspond with its physiological activity.</p>
<p><bold>Significance:</bold>
This work strengthens the therapeutic relevance of using CDNF to treat neurodegenerative diseases.</p>
</div>
</front>
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