The E3 ubiquitin ligase parkin is recruited to the 26 S proteasome via the proteasomal ubiquitin receptor Rpn13.
Identifieur interne : 000515 ( Main/Exploration ); précédent : 000514; suivant : 000516The E3 ubiquitin ligase parkin is recruited to the 26 S proteasome via the proteasomal ubiquitin receptor Rpn13.
Auteurs : Miguel A. Aguileta [Canada] ; Jelena Korac [Croatie] ; Thomas M. Durcan [Canada] ; Jean-François Trempe [Canada] ; Michael Haber [Canada] ; Kalle Gehring [Canada] ; Suzanne Elsasser ; Oliver Waidmann [Allemagne] ; Edward A. Fon [Canada] ; Koraljka Husnjak [Allemagne]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2015.
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : Proteasome Endopeptidase Complex.
- chemical , metabolism : Membrane Glycoproteins, Proteasome Endopeptidase Complex, Ubiquitin-Protein Ligases.
- Base Sequence, HEK293 Cells, Humans, Magnetic Resonance Spectroscopy, Surface Plasmon Resonance, Two-Hybrid System Techniques.
Abstract
Mutations in the Park2 gene, encoding the RING-HECT hybrid E3 ubiquitin ligase parkin, are responsible for a common familial form of Parkinson disease. By mono- and polyubiquitinating target proteins, parkin regulates various cellular processes, including degradation of proteins within the 26 S proteasome, a large multimeric degradation machine. In our attempt to further elucidate the function of parkin, we have identified the proteasomal ubiquitin receptor Rpn13/ADRM1 as a parkin-interacting protein. We show that the N-terminal ubiquitin-like (Ubl) domain of parkin binds directly to the pleckstrin-like receptor for ubiquitin (Pru) domain within Rpn13. Using mutational analysis and NMR, we find that Pru binding involves the hydrophobic patch surrounding Ile-44 in the parkin Ubl, a region that is highly conserved between ubiquitin and Ubl domains. However, compared with ubiquitin, the parkin Ubl exhibits greater than 10-fold higher affinity for the Pru domain. Moreover, knockdown of Rpn13 in cells increases parkin levels and abrogates parkin recruitment to the 26 S proteasome, establishing Rpn13 as the major proteasomal receptor for parkin. In contrast, silencing Rpn13 did not impair parkin recruitment to mitochondria or parkin-mediated mitophagy upon carbonyl cyanide m-chlorophenyl hydrazone-induced mitochondrial depolarization. However, it did delay the clearance of mitochondrial proteins (TIM23, TIM44, and TOM20) and enhance parkin autoubiquitination. Taken together, these findings implicate Rpn13 in linking parkin to the 26 S proteasome and regulating the clearance of mitochondrial proteins during mitophagy.
DOI: 10.1074/jbc.M114.614925
PubMed: 25666615
Affiliations:
- Allemagne, Canada, Croatie
- District de Darmstadt, Hesse (Land), Québec
- Francfort-sur-le-Main, Montréal
- Université McGill
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Aguileta</name><affiliation wicri:level="4"><nlm:affiliation>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Korac, Jelena" sort="Korac, Jelena" uniqKey="Korac J" first="Jelena" last="Korac">Jelena Korac</name><affiliation wicri:level="1"><nlm:affiliation>the School of Medicine, University of Split, 21000 Split, Croatia.</nlm:affiliation><country xml:lang="fr">Croatie</country><wicri:regionArea>the School of Medicine, University of Split, 21000 Split</wicri:regionArea><wicri:noRegion>21000 Split</wicri:noRegion></affiliation></author><author><name sortKey="Durcan, Thomas M" sort="Durcan, Thomas M" uniqKey="Durcan T" first="Thomas M" last="Durcan">Thomas M. Durcan</name><affiliation wicri:level="4"><nlm:affiliation>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Trempe, Jean Francois" sort="Trempe, Jean Francois" uniqKey="Trempe J" first="Jean-François" last="Trempe">Jean-François Trempe</name><affiliation wicri:level="4"><nlm:affiliation>the Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>the Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Haber, Michael" sort="Haber, Michael" uniqKey="Haber M" first="Michael" last="Haber">Michael Haber</name><affiliation wicri:level="4"><nlm:affiliation>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Gehring, Kalle" sort="Gehring, Kalle" uniqKey="Gehring K" first="Kalle" last="Gehring">Kalle Gehring</name><affiliation wicri:level="4"><nlm:affiliation>the Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>the Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Elsasser, Suzanne" sort="Elsasser, Suzanne" uniqKey="Elsasser S" first="Suzanne" last="Elsasser">Suzanne Elsasser</name><affiliation><nlm:affiliation>the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Waidmann, Oliver" sort="Waidmann, Oliver" uniqKey="Waidmann O" first="Oliver" last="Waidmann">Oliver Waidmann</name><affiliation wicri:level="3"><nlm:affiliation>Goethe University Medical School, D-60590 Frankfurt am Main, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Goethe University Medical School, D-60590 Frankfurt am Main</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><affiliation wicri:level="4"><nlm:affiliation>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>From the McGill Parkinson Program and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Husnjak, Koraljka" sort="Husnjak, Koraljka" uniqKey="Husnjak K" first="Koraljka" last="Husnjak">Koraljka Husnjak</name><affiliation wicri:level="3"><nlm:affiliation>Goethe University Medical School, D-60590 Frankfurt am Main, Germany husnjak@biochem2.de.</nlm:affiliation><country wicri:rule="url">Allemagne</country><wicri:regionArea>Goethe University Medical School, D-60590 Frankfurt am Main</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region><settlement type="city">Francfort-sur-le-Main</settlement></placeName></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Base Sequence</term><term>HEK293 Cells</term><term>Humans</term><term>Magnetic Resonance Spectroscopy</term><term>Membrane Glycoproteins (metabolism)</term><term>Proteasome Endopeptidase Complex (genetics)</term><term>Proteasome Endopeptidase Complex (metabolism)</term><term>Surface Plasmon Resonance</term><term>Two-Hybrid System Techniques</term><term>Ubiquitin-Protein Ligases (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Proteasome Endopeptidase Complex</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Membrane Glycoproteins</term><term>Proteasome Endopeptidase Complex</term><term>Ubiquitin-Protein Ligases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Base Sequence</term><term>HEK293 Cells</term><term>Humans</term><term>Magnetic Resonance Spectroscopy</term><term>Surface Plasmon Resonance</term><term>Two-Hybrid System Techniques</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mutations in the Park2 gene, encoding the RING-HECT hybrid E3 ubiquitin ligase parkin, are responsible for a common familial form of Parkinson disease. By mono- and polyubiquitinating target proteins, parkin regulates various cellular processes, including degradation of proteins within the 26 S proteasome, a large multimeric degradation machine. In our attempt to further elucidate the function of parkin, we have identified the proteasomal ubiquitin receptor Rpn13/ADRM1 as a parkin-interacting protein. We show that the N-terminal ubiquitin-like (Ubl) domain of parkin binds directly to the pleckstrin-like receptor for ubiquitin (Pru) domain within Rpn13. Using mutational analysis and NMR, we find that Pru binding involves the hydrophobic patch surrounding Ile-44 in the parkin Ubl, a region that is highly conserved between ubiquitin and Ubl domains. However, compared with ubiquitin, the parkin Ubl exhibits greater than 10-fold higher affinity for the Pru domain. Moreover, knockdown of Rpn13 in cells increases parkin levels and abrogates parkin recruitment to the 26 S proteasome, establishing Rpn13 as the major proteasomal receptor for parkin. In contrast, silencing Rpn13 did not impair parkin recruitment to mitochondria or parkin-mediated mitophagy upon carbonyl cyanide m-chlorophenyl hydrazone-induced mitochondrial depolarization. However, it did delay the clearance of mitochondrial proteins (TIM23, TIM44, and TOM20) and enhance parkin autoubiquitination. Taken together, these findings implicate Rpn13 in linking parkin to the 26 S proteasome and regulating the clearance of mitochondrial proteins during mitophagy.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Canada</li><li>Croatie</li></country><region><li>District de Darmstadt</li><li>Hesse (Land)</li><li>Québec</li></region><settlement><li>Francfort-sur-le-Main</li><li>Montréal</li></settlement><orgName><li>Université McGill</li></orgName></list><tree><noCountry><name sortKey="Elsasser, Suzanne" sort="Elsasser, Suzanne" uniqKey="Elsasser S" first="Suzanne" last="Elsasser">Suzanne Elsasser</name></noCountry><country name="Canada"><region name="Québec"><name sortKey="Aguileta, Miguel A" sort="Aguileta, Miguel A" uniqKey="Aguileta M" first="Miguel A" last="Aguileta">Miguel A. Aguileta</name></region><name sortKey="Durcan, Thomas M" sort="Durcan, Thomas M" uniqKey="Durcan T" first="Thomas M" last="Durcan">Thomas M. Durcan</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><name sortKey="Gehring, Kalle" sort="Gehring, Kalle" uniqKey="Gehring K" first="Kalle" last="Gehring">Kalle Gehring</name><name sortKey="Haber, Michael" sort="Haber, Michael" uniqKey="Haber M" first="Michael" last="Haber">Michael Haber</name><name sortKey="Trempe, Jean Francois" sort="Trempe, Jean Francois" uniqKey="Trempe J" first="Jean-François" last="Trempe">Jean-François Trempe</name></country><country name="Croatie"><noRegion><name sortKey="Korac, Jelena" sort="Korac, Jelena" uniqKey="Korac J" first="Jelena" last="Korac">Jelena Korac</name></noRegion></country><country name="Allemagne"><region name="Hesse (Land)"><name sortKey="Waidmann, Oliver" sort="Waidmann, Oliver" uniqKey="Waidmann O" first="Oliver" last="Waidmann">Oliver Waidmann</name></region><name sortKey="Husnjak, Koraljka" sort="Husnjak, Koraljka" uniqKey="Husnjak K" first="Koraljka" last="Husnjak">Koraljka Husnjak</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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