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Refining the minimal sequence required for ERK1/2-dependent poly-ubiquitination and proteasome-dependent turnover of BIM
- Source :
- Cellular Signalling. 22:801-808
- Publication Year :
- 2010
- Publisher :
- Elsevier BV, 2010.
-
Abstract
- The pro-apoptotic protein BIM(EL) is phosphorylated by ERK1/2 and this targets the protein for poly-ubiquitination and degradation by the proteasome as a survival mechanism. To define in greater detail the sequence determinants required for BIM(EL) turnover we have compared various BIM splice variants and truncation mutants. Of the naturally occurring splice variants BIMbeta1, which lacks the C-terminal hydrophobic domain, the BH3 domain and is cytosolic, exhibited the fastest turnover rate. Indeed, neither the C-terminus, the BH3 domain nor the DLC1 binding region was required for poly-ubiquitination and turnover of BIM. However, we demonstrate that a region consisting of the ERK1/2 docking domain, ERK1/2 phosphorylation sites and either of the two potential ubiquitin-acceptor lysine residues is sufficient to allow poly-ubiquitination and turnover of BIM. In the process we demonstrate that the C-terminal hydrophobic domain, previously suggested to be important in membrane localisation, is as important as the BH3 domain for BIM to induce cell death; similarly, the pro-death BH3-domain can also confer correct mitochondrial localisation in the absence of the C-terminus. These results refine the minimal sequence for ERK1/2-driven degradation and further define the functional importance of key regions within BIM(EL), highlighting the complexity of this pro-apoptotic protein.
- Subjects :
- Proteasome Endopeptidase Complex
Mutant
Apoptosis
Cell Line
Structure-Activity Relationship
Protein structure
Ubiquitin
Proto-Oncogene Proteins
Humans
Amino Acid Sequence
Phosphorylation
Polyubiquitin
Peptide sequence
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Bcl-2-Like Protein 11
biology
Ubiquitination
Membrane Proteins
Cell Biology
Mitochondria
Protein Structure, Tertiary
Transport protein
Cell biology
Enzyme Activation
Alternative Splicing
Protein Transport
Proteasome
Biochemistry
Mutagenesis
biology.protein
DLC1
biological phenomena, cell phenomena, and immunity
Apoptosis Regulatory Proteins
Hydrophobic and Hydrophilic Interactions
Protein Processing, Post-Translational
Signal Transduction
Subjects
Details
- ISSN :
- 08986568
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Cellular Signalling
- Accession number :
- edsair.doi.dedup.....ef5f9e9acff54113f7f291fb5f5265b8