The fast-mobility isoform of mouse Mcl-1 is a mitochondrial matrix-localized protein with attenuated anti-apoptotic activity

FEBS Lett. 2010 Aug 4;584(15):3323-30. doi: 10.1016/j.febslet.2010.07.013. Epub 2010 Jul 11.

Abstract

The full-length pro-survival protein Mcl-1 predominantly resides on the outer membrane of mitochondria. Here, we identified a mitochondrial matrix-localized isoform of Mcl-1 that lacks 33 amino acid residues at the N-terminus which serve both as a mitochondrial targeting and processing signal. Ectopically-expressed Mcl-1 without the N-terminal 33 residues failed to enter the mitochondrial matrix but retained wt-like activities both for interaction with BH3-only proteins and anti-apoptosis. In contrast, the mitochondrial matrix-localized isoform failed to interact with BH3-only proteins and manifested an attenuated anti-apoptotic activity. This study reveals that import of Mcl-1 into the mitochondrial matrix results in the attenuation of Mcl-1's anti-apoptotic function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Bcl-2-Like Protein 11
  • HeLa Cells
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Membrane Proteins / metabolism
  • Metalloendopeptidases / metabolism
  • Mice
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Mitochondrial Processing Peptidase
  • Mutant Proteins / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Binding
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational
  • Protein Sorting Signals
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Sequence Deletion
  • Subcellular Fractions / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Mcl1 protein, mouse
  • Membrane Proteins
  • Mutant Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • PUMA protein, mouse
  • Pmaip1 protein, mouse
  • Protein Isoforms
  • Protein Sorting Signals
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Proteins
  • Metalloendopeptidases