Source:http://linkedlifedata.com/resource/pubmed/id/21378313
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
Pt 6
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pubmed:dateCreated |
2011-3-7
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pubmed:abstractText |
BIM-extra long (BIM(EL)), a pro-apoptotic BH3-only protein and part of the BCL-2 family, is degraded by the proteasome following activation of the ERK1/2 signalling pathway. Although studies have demonstrated poly-ubiquitylation of BIM(EL) in cells, the nature of the ubiquitin chain linkage has not been defined. Using ubiquitin-binding domains (UBDs) specific for defined ubiquitin chain linkages, we show that BIM(EL) undergoes K48-linked poly-ubiquitylation at either of two lysine residues. Surprisingly, BIM(EL)?KK, which lacks both lysine residues, was not poly-ubiquitylated but still underwent ERK1/2-driven, proteasome-dependent turnover. BIM has been proposed to be an intrinsically disordered protein (IDP) and some IDPs can be degraded by uncapped 20S proteasomes in the absence of poly-ubiquitylation. We show that BIM(EL) is degraded by isolated 20S proteasomes but that this is prevented when BIM(EL) is bound to its pro-survival target protein MCL-1. Furthermore, knockdown of the proteasome cap component Rpn2 does not prevent BIM(EL) turnover in cells, and inhibition of the E3 ubiquitin ligase ?-TrCP, which catalyses poly-Ub of BIM(EL), causes Cdc25A accumulation but does not inhibit BIM(EL) turnover. These results provide new insights into the regulation of BIM(EL) by defining a novel ubiquitin-independent pathway for the proteasome-dependent destruction of this highly toxic protein.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Apoptosis Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Bcl-2-like protein 11,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1477-9137
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
124
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
969-77
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pubmed:meshHeading |
pubmed-meshheading:21378313-Animals,
pubmed-meshheading:21378313-Apoptosis Regulatory Proteins,
pubmed-meshheading:21378313-Cell Line,
pubmed-meshheading:21378313-Membrane Proteins,
pubmed-meshheading:21378313-Mice,
pubmed-meshheading:21378313-Mice, Knockout,
pubmed-meshheading:21378313-Mitogen-Activated Protein Kinase 1,
pubmed-meshheading:21378313-Mitogen-Activated Protein Kinase 3,
pubmed-meshheading:21378313-Proteasome Endopeptidase Complex,
pubmed-meshheading:21378313-Proto-Oncogene Proteins,
pubmed-meshheading:21378313-Ubiquitination
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pubmed:year |
2011
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pubmed:articleTitle |
BIM(EL), an intrinsically disordered protein, is degraded by 20S proteasomes in the absence of poly-ubiquitylation.
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pubmed:affiliation |
Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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