PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity
PINK1 kinase activates the E3 ubiquitin ligase Parkin to induce selective autophagy of damaged mitochondria. However, it has been unclear how PINK1 activates and recruits Parkin to mitochondria. Although PINK1 phosphorylates Parkin, other PINK1 substrates appear to activate Parkin, as the mutation o...
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| Veröffentlicht in: | The Journal of cell biology 2014-04, Vol.205 (2), p.143-153 |
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| container_title | The Journal of cell biology |
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| creator | Kane, Lesley A Lazarou, Michael Fogel, Adam I Li, Yan Yamano, Koji Sarraf, Shireen A Banerjee, Soojay Youle, Richard J |
| description | PINK1 kinase activates the E3 ubiquitin ligase Parkin to induce selective autophagy of damaged mitochondria. However, it has been unclear how PINK1 activates and recruits Parkin to mitochondria. Although PINK1 phosphorylates Parkin, other PINK1 substrates appear to activate Parkin, as the mutation of all serine and threonine residues conserved between Drosophila and human, including Parkin S65, did not wholly impair Parkin translocation to mitochondria. Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. In cells, the phosphomimetic ubiquitin mutant S65D bound and activated Parkin. Furthermore, expression of ubiquitin S65A, a mutant that cannot be phosphorylated by PINK1, inhibited Parkin translocation to damaged mitochondria. These results explain a feed-forward mechanism of PINK1-mediated initiation of Parkin E3 ligase activity. |
| doi_str_mv | 10.1083/jcb.201402104 |
| format | Article |
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However, it has been unclear how PINK1 activates and recruits Parkin to mitochondria. Although PINK1 phosphorylates Parkin, other PINK1 substrates appear to activate Parkin, as the mutation of all serine and threonine residues conserved between Drosophila and human, including Parkin S65, did not wholly impair Parkin translocation to mitochondria. Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. In cells, the phosphomimetic ubiquitin mutant S65D bound and activated Parkin. Furthermore, expression of ubiquitin S65A, a mutant that cannot be phosphorylated by PINK1, inhibited Parkin translocation to damaged mitochondria. These results explain a feed-forward mechanism of PINK1-mediated initiation of Parkin E3 ligase activity.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.201402104</identifier><identifier>PMID: 24751536</identifier><identifier>CODEN: JCLBA3</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Amino Acid Substitution ; Animals ; Biochemistry ; Cell Line ; Drosophila ; Drosophila melanogaster ; Enzyme Activation - physiology ; Gene expression ; Humans ; Kinases ; Mass spectrometry ; Mitochondria ; Mutation ; Mutation, Missense ; Phosphorylation ; Phosphorylation - physiology ; Protein Kinases - genetics ; Protein Kinases - metabolism ; Protein Structure, Tertiary ; Ubiquitin - genetics ; Ubiquitin - metabolism ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>The Journal of cell biology, 2014-04, Vol.205 (2), p.143-153</ispartof><rights>Copyright Rockefeller University Press Apr 28, 2014</rights><rights>2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c514t-2680261ee7b61281979b36cb4604ce00c2819b898e088f51fc38dca827dbf36b3</citedby><cites>FETCH-LOGICAL-c514t-2680261ee7b61281979b36cb4604ce00c2819b898e088f51fc38dca827dbf36b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24751536$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kane, Lesley A</creatorcontrib><creatorcontrib>Lazarou, Michael</creatorcontrib><creatorcontrib>Fogel, Adam I</creatorcontrib><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Yamano, Koji</creatorcontrib><creatorcontrib>Sarraf, Shireen A</creatorcontrib><creatorcontrib>Banerjee, Soojay</creatorcontrib><creatorcontrib>Youle, Richard J</creatorcontrib><title>PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>PINK1 kinase activates the E3 ubiquitin ligase Parkin to induce selective autophagy of damaged mitochondria. However, it has been unclear how PINK1 activates and recruits Parkin to mitochondria. Although PINK1 phosphorylates Parkin, other PINK1 substrates appear to activate Parkin, as the mutation of all serine and threonine residues conserved between Drosophila and human, including Parkin S65, did not wholly impair Parkin translocation to mitochondria. Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. In cells, the phosphomimetic ubiquitin mutant S65D bound and activated Parkin. Furthermore, expression of ubiquitin S65A, a mutant that cannot be phosphorylated by PINK1, inhibited Parkin translocation to damaged mitochondria. These results explain a feed-forward mechanism of PINK1-mediated initiation of Parkin E3 ligase activity.</description><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Cell Line</subject><subject>Drosophila</subject><subject>Drosophila melanogaster</subject><subject>Enzyme Activation - physiology</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Kinases</subject><subject>Mass spectrometry</subject><subject>Mitochondria</subject><subject>Mutation</subject><subject>Mutation, Missense</subject><subject>Phosphorylation</subject><subject>Phosphorylation - physiology</subject><subject>Protein Kinases - genetics</subject><subject>Protein Kinases - metabolism</subject><subject>Protein Structure, Tertiary</subject><subject>Ubiquitin - genetics</subject><subject>Ubiquitin - metabolism</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1LAzEQxYMoWj-OXmXBi5fVmSS7m14EKVWLUnvQc0jSrKZud2uyW-h_b0prUQ9DmDc_HjN5hJwjXCMIdjMz-poCcqAIfI_0MOOQitjvkx5EMe1nNDsixyHMAIAXnB2SI8qLDDOW98h4Mho_YbL4aEIsv6pUa0PSaffVudbVSdskyrRuGeVkovxnlIbs17xy7yrYDePa1Sk5KFUV7Nn2PSFv98PXwWP6_PIwGtw9pyZD3qY0F0BztLbQOVKB_aKvWW40z4EbC2DWmhZ9YUGIMsPSMDE1StBiqkuWa3ZCbje-i07P7dTYuvWqkgvv5sqvZKOc_Dup3Yd8b5aSAzDKs2hwtTXwzVdnQyvnLhhbVaq2TRdk_EYOiAXDiF7-Q2dN5-t4XqQoK5AWYm2YbijjmxC8LXfLIMh1UjImJXdJRf7i9wU7-ica9g15j45Y</recordid><startdate>20140428</startdate><enddate>20140428</enddate><creator>Kane, Lesley A</creator><creator>Lazarou, Michael</creator><creator>Fogel, Adam I</creator><creator>Li, Yan</creator><creator>Yamano, Koji</creator><creator>Sarraf, Shireen A</creator><creator>Banerjee, Soojay</creator><creator>Youle, Richard J</creator><general>Rockefeller University Press</general><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20140428</creationdate><title>PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity</title><author>Kane, Lesley A ; Lazarou, Michael ; Fogel, Adam I ; Li, Yan ; Yamano, Koji ; Sarraf, Shireen A ; Banerjee, Soojay ; Youle, Richard J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c514t-2680261ee7b61281979b36cb4604ce00c2819b898e088f51fc38dca827dbf36b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Cell Line</topic><topic>Drosophila</topic><topic>Drosophila melanogaster</topic><topic>Enzyme Activation - physiology</topic><topic>Gene expression</topic><topic>Humans</topic><topic>Kinases</topic><topic>Mass spectrometry</topic><topic>Mitochondria</topic><topic>Mutation</topic><topic>Mutation, Missense</topic><topic>Phosphorylation</topic><topic>Phosphorylation - physiology</topic><topic>Protein Kinases - genetics</topic><topic>Protein Kinases - metabolism</topic><topic>Protein Structure, Tertiary</topic><topic>Ubiquitin - genetics</topic><topic>Ubiquitin - metabolism</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kane, Lesley A</creatorcontrib><creatorcontrib>Lazarou, Michael</creatorcontrib><creatorcontrib>Fogel, Adam I</creatorcontrib><creatorcontrib>Li, Yan</creatorcontrib><creatorcontrib>Yamano, Koji</creatorcontrib><creatorcontrib>Sarraf, Shireen A</creatorcontrib><creatorcontrib>Banerjee, Soojay</creatorcontrib><creatorcontrib>Youle, Richard J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kane, Lesley A</au><au>Lazarou, Michael</au><au>Fogel, Adam I</au><au>Li, Yan</au><au>Yamano, Koji</au><au>Sarraf, Shireen A</au><au>Banerjee, Soojay</au><au>Youle, Richard J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2014-04-28</date><risdate>2014</risdate><volume>205</volume><issue>2</issue><spage>143</spage><epage>153</epage><pages>143-153</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><coden>JCLBA3</coden><abstract>PINK1 kinase activates the E3 ubiquitin ligase Parkin to induce selective autophagy of damaged mitochondria. However, it has been unclear how PINK1 activates and recruits Parkin to mitochondria. Although PINK1 phosphorylates Parkin, other PINK1 substrates appear to activate Parkin, as the mutation of all serine and threonine residues conserved between Drosophila and human, including Parkin S65, did not wholly impair Parkin translocation to mitochondria. Using mass spectrometry, we discovered that endogenous PINK1 phosphorylated ubiquitin at serine 65, homologous to the site phosphorylated by PINK1 in Parkin's ubiquitin-like domain. Recombinant TcPINK1 directly phosphorylated ubiquitin and phospho-ubiquitin activated Parkin E3 ubiquitin ligase activity in cell-free assays. In cells, the phosphomimetic ubiquitin mutant S65D bound and activated Parkin. Furthermore, expression of ubiquitin S65A, a mutant that cannot be phosphorylated by PINK1, inhibited Parkin translocation to damaged mitochondria. 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| subjects | Amino Acid Substitution Animals Biochemistry Cell Line Drosophila Drosophila melanogaster Enzyme Activation - physiology Gene expression Humans Kinases Mass spectrometry Mitochondria Mutation Mutation, Missense Phosphorylation Phosphorylation - physiology Protein Kinases - genetics Protein Kinases - metabolism Protein Structure, Tertiary Ubiquitin - genetics Ubiquitin - metabolism Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism |
| title | PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity |
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