Iron-mediated Aggregation and a Localized Structural Change Characterize Ferritin from a Mutant Light Chain Polypeptide That Causes Neurodegeneration*
Identifieur interne : 002973 ( Main/Exploration ); précédent : 002972; suivant : 002974Iron-mediated Aggregation and a Localized Structural Change Characterize Ferritin from a Mutant Light Chain Polypeptide That Causes Neurodegeneration*
Auteurs : Martin A. Baraibar ; Ana G. Barbeito ; Barry B. Muhoberac [États-Unis] ; Ruben VidalSource :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2008.
Descripteurs français
- KwdFr :
- Animaux, Cellules cultivées, Dichroïsme circulaire, Dégénérescence nerveuse (anatomopathologie), Dégénérescence nerveuse (génétique), Dégénérescence nerveuse (métabolisme), Dénaturation des protéines, Fer (métabolisme), Ferritines (), Ferritines (génétique), Ferritines (métabolisme), Ferritines (ultrastructure), Humains, Liaison aux protéines, Microscopie électronique à transmission, Mutation (génétique), Peptides (), Peptides (génétique), Peptides (métabolisme), Souris, Température.
- MESH :
- anatomopathologie : Dégénérescence nerveuse.
- génétique : Dégénérescence nerveuse, Ferritines, Mutation, Peptides.
- métabolisme : Dégénérescence nerveuse, Fer, Ferritines, Peptides.
- ultrastructure : Ferritines.
- Animaux, Cellules cultivées, Dichroïsme circulaire, Dénaturation des protéines, Ferritines, Humains, Liaison aux protéines, Microscopie électronique à transmission, Peptides, Souris, Température.
English descriptors
- KwdEn :
- Animals, Cells, Cultured, Circular Dichroism, Ferritins (chemistry), Ferritins (genetics), Ferritins (metabolism), Ferritins (ultrastructure), Humans, Iron (metabolism), Mice, Microscopy, Electron, Transmission, Mutation (genetics), Nerve Degeneration (genetics), Nerve Degeneration (metabolism), Nerve Degeneration (pathology), Peptides (chemistry), Peptides (genetics), Peptides (metabolism), Protein Binding, Protein Denaturation, Temperature.
- MESH :
- chemical , chemistry : Ferritins, Peptides.
- chemical , genetics : Ferritins, Peptides.
- chemical , metabolism : Ferritins, Iron, Peptides.
- chemical , ultrastructure : Ferritins.
- genetics : Mutation, Nerve Degeneration.
- metabolism : Nerve Degeneration.
- pathology : Nerve Degeneration.
- Animals, Cells, Cultured, Circular Dichroism, Humans, Mice, Microscopy, Electron, Transmission, Protein Binding, Protein Denaturation, Temperature.
Abstract
Nucleotide insertions in the ferritin light chain (FTL) polypeptide gene
cause hereditary ferritinopathy, a neurodegenerative disease characterized by
abnormal accumulation of ferritin and iron in the central nervous system. Here
we describe for the first time the protein structure and iron storage function
of the FTL mutant
Url:
DOI: 10.1074/jbc.M805532200
PubMed: 18755684
PubMed Central: 2581579
Affiliations:
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Le document en format XML
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Ferritin from a Mutant Light Chain Polypeptide That Causes
Neurodegeneration<xref ref-type="fn" rid="fn1">*</xref><xref ref-type="fn" rid="fn2"></xref></title><author><name sortKey="Baraibar, Martin A" sort="Baraibar, Martin A" uniqKey="Baraibar M" first="Martin A." last="Baraibar">Martin A. Baraibar</name><affiliation><nlm:aff id="N0x1cd40b0N0x1f57ec0">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine and the</nlm:aff><wicri:noCountry code="subfield">Indiana University School of Medicine and the</wicri:noCountry></affiliation></author><author><name sortKey="Barbeito, Ana G" sort="Barbeito, Ana G" uniqKey="Barbeito A" first="Ana G." last="Barbeito">Ana G. Barbeito</name><affiliation><nlm:aff id="N0x1cd40b0N0x1f57ec0">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine and the</nlm:aff><wicri:noCountry code="subfield">Indiana University School of Medicine and the</wicri:noCountry></affiliation></author><author><name sortKey="Muhoberac, Barry B" sort="Muhoberac, Barry B" uniqKey="Muhoberac B" first="Barry B." last="Muhoberac">Barry B. Muhoberac</name><affiliation wicri:level="2"><nlm:aff id="N0x1cd40b0N0x1f57ec0">Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Indiana</region></placeName><wicri:cityArea>Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis, Indianapolis</wicri:cityArea></affiliation></author><author><name sortKey="Vidal, Ruben" sort="Vidal, Ruben" uniqKey="Vidal R" first="Ruben" last="Vidal">Ruben Vidal</name><affiliation><nlm:aff id="N0x1cd40b0N0x1f57ec0">Department of Pathology and Laboratory Medicine, Indiana University School of Medicine and the</nlm:aff><wicri:noCountry code="subfield">Indiana University School of Medicine and the</wicri:noCountry></affiliation></author></analytic><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="2008">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>Circular Dichroism</term><term>Ferritins (chemistry)</term><term>Ferritins (genetics)</term><term>Ferritins (metabolism)</term><term>Ferritins (ultrastructure)</term><term>Humans</term><term>Iron (metabolism)</term><term>Mice</term><term>Microscopy, Electron, Transmission</term><term>Mutation (genetics)</term><term>Nerve Degeneration (genetics)</term><term>Nerve Degeneration (metabolism)</term><term>Nerve Degeneration (pathology)</term><term>Peptides (chemistry)</term><term>Peptides (genetics)</term><term>Peptides (metabolism)</term><term>Protein Binding</term><term>Protein Denaturation</term><term>Temperature</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules cultivées</term><term>Dichroïsme circulaire</term><term>Dégénérescence nerveuse (anatomopathologie)</term><term>Dégénérescence nerveuse (génétique)</term><term>Dégénérescence nerveuse (métabolisme)</term><term>Dénaturation des protéines</term><term>Fer (métabolisme)</term><term>Ferritines ()</term><term>Ferritines (génétique)</term><term>Ferritines (métabolisme)</term><term>Ferritines (ultrastructure)</term><term>Humains</term><term>Liaison aux protéines</term><term>Microscopie électronique à transmission</term><term>Mutation (génétique)</term><term>Peptides ()</term><term>Peptides (génétique)</term><term>Peptides (métabolisme)</term><term>Souris</term><term>Température</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Ferritins</term><term>Peptides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Ferritins</term><term>Peptides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Ferritins</term><term>Iron</term><term>Peptides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="ultrastructure" xml:lang="en"><term>Ferritins</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Dégénérescence nerveuse</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Mutation</term><term>Nerve Degeneration</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Dégénérescence nerveuse</term><term>Ferritines</term><term>Mutation</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Nerve Degeneration</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Dégénérescence nerveuse</term><term>Fer</term><term>Ferritines</term><term>Peptides</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Nerve Degeneration</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="fr"><term>Ferritines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cells, Cultured</term><term>Circular Dichroism</term><term>Humans</term><term>Mice</term><term>Microscopy, Electron, Transmission</term><term>Protein Binding</term><term>Protein Denaturation</term><term>Temperature</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules cultivées</term><term>Dichroïsme circulaire</term><term>Dénaturation des protéines</term><term>Ferritines</term><term>Humains</term><term>Liaison aux protéines</term><term>Microscopie électronique à transmission</term><term>Peptides</term><term>Souris</term><term>Température</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Nucleotide insertions in the ferritin light chain (FTL) polypeptide gene
cause hereditary ferritinopathy, a neurodegenerative disease characterized by
abnormal accumulation of ferritin and iron in the central nervous system. Here
we describe for the first time the protein structure and iron storage function
of the FTL mutant <italic>p.Phe167SerfsX26</italic> (MT-FTL), which has a C terminus
altered in sequence and extended in length. MT-FTL polypeptides assembled
spontaneously into soluble, spherical 24-mers that were ultrastructurally
indistinguishable from those of the wild type. Far-UV CD showed a decrease in
α-helical content, and 8-anilino-1-naphthalenesulfonate fluorescence
revealed the appearance of hydrophobic binding sites. Near-UV CD and
proteolysis studies suggested little or no structural alteration outside of
the C-terminal region. In contrast to wild type, MT-FTL homopolymers
precipitated at much lower iron loading, had a diminished capacity to
incorporate iron, and were less thermostable. However, precipitation was
significantly reversed by addition of iron chelators both <italic>in vitro</italic>and <italic>in vivo</italic>. Our results reveal substantial protein conformational
changes localized at the 4-fold pore of MT-FTL homopolymers and imply that the
C terminus of the MT-FTL polypeptide plays an important role in ferritin
solubility, stability, and iron management. We propose that the protrusion of
some portion of the C terminus above the spherical shell allows it to
cross-link with other mutant polypeptides through iron bridging, leading to
enhanced mutant precipitation by iron. Our data suggest that hereditary
ferritinopathy pathogenesis is likely to result from a combination of
reduction in iron storage function and enhanced toxicity associated with
iron-induced ferritin aggregates.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Indiana</li></region></list><tree><noCountry><name sortKey="Baraibar, Martin A" sort="Baraibar, Martin A" uniqKey="Baraibar M" first="Martin A." last="Baraibar">Martin A. Baraibar</name><name sortKey="Barbeito, Ana G" sort="Barbeito, Ana G" uniqKey="Barbeito A" first="Ana G." last="Barbeito">Ana G. Barbeito</name><name sortKey="Vidal, Ruben" sort="Vidal, Ruben" uniqKey="Vidal R" first="Ruben" last="Vidal">Ruben Vidal</name></noCountry><country name="États-Unis"><region name="Indiana"><name sortKey="Muhoberac, Barry B" sort="Muhoberac, Barry B" uniqKey="Muhoberac B" first="Barry B." last="Muhoberac">Barry B. Muhoberac</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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