Abstract
Mcl-1 functions at an apical step in many regulatory programs that control cell death. Although the mitochondrion is one major subcellular organelle where Mcl-1 functions, the molecular mechanism by which Mcl-1 is targeted to mitochondria remains unclear. Here, we demonstrate that Mcl-1 is loosely associated with the outer membrane of mitochondria. Furthermore, we demonstrate that Mcl-1 interacts with the mitochondrial import receptor Tom70, and such interaction requires an internal domain of Mcl-1 that contains an EELD motif. A Tom70 antibody that blocks Mcl-1-Tom70 interaction blocks mitochondrial import of Mcl-1 in vitro. Furthermore, Mcl-1 is significantly less targeted to mitochondria in Tom70 knockdown than in the control cells. Similar targeting preference is also observed for the DM mutant of Mcl-1 whose mutation at the EELD motif markedly attenuates its Tom70 binding activity. Together, our results indicate that the internal EELD domain facilitates mitochondrial targeting of Mcl-1 via a Tom70-dependent pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Cells, Cultured
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Humans
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K562 Cells
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Membrane Transport Proteins
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Mice
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Mice, Inbred C57BL
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Mitochondria / metabolism*
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Membranes / metabolism
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Mitochondrial Precursor Protein Import Complex Proteins
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Mitochondrial Proteins / metabolism*
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Mutant Proteins / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / chemistry*
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Neoplasm Proteins / metabolism*
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Protein Binding
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Protein Interaction Mapping
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Protein Structure, Tertiary
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Protein Transport
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Proto-Oncogene Proteins c-bcl-2 / chemistry*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Thermodynamics
Substances
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Mcl1 protein, mouse
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Membrane Transport Proteins
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Precursor Protein Import Complex Proteins
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Mitochondrial Proteins
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Mutant Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Cytoplasmic and Nuclear
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TOMM70 protein, human