J. Biol. Chem., Vol. 268, Issue 34, 25265-25268, Dec, 1993
Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH- terminal signal anchor sequence
M Nguyen, DG Millar, VW Yong, SJ Korsmeyer and GC Shore
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
The protooncogene product Bcl-2 is an integral membrane protein that
functions as a suppressor of programmed cell death. It contains a single
predicted transmembrane segment located at its COOH terminus. Here, we show
that the transmembrane domain of human Bcl-2 functions as a mitochondrial
signal anchor sequence that targets and inserts the protein into the outer
membrane in an Ncyto-C(in) orientation, leaving the bulk of the polypeptide
facing the cytosol. Deletion of the COOH- terminal 22 amino acids of Bcl-2
abrogated protein targeting, whereas fusion of this domain to the COOH
terminus of dihydrofolate reductase resulted in targeting and insertion of
the hybrid protein into the outer membrane in a manner similar to that of
Bcl-2. The sequence of the hydrophobic core of the Bcl-2 signal anchor is
similar to the corresponding region of the NH2-terminal signal anchor of
the mitochondrial outer membrane protein in yeast, Mas70p. A synthetic
peptide comprising the Mas70p signal anchor sequence effectively competed
for insertion of Bcl-2 into the outer membrane but had no effect on the
comparatively low association that Bcl-2 makes with endoplasmic reticulum
microsomes. Insertion of Bcl-2 into the mitochondrial outer membrane is
mechanistically different than its association with microsomes.
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