A 15-residue bifunctional element in D-AKAP1 is required for both endoplasmic reticulum and mitochondrial targeting.
The cAMP-dependent protein kinase anchoring protein, d-AKAP1, has two N-terminal splice variants. The shorter forms (N0, d-AKAP1a, and -1c) target to mitochondria, and the longer forms (N1, d-AKAP1b, and -1d) with 33 additional residues N-terminal to N0 target to the endoplasmic reticulum (ER) (Huang, L. J., Wang, L., Ma, Y., Durick, K., Perkins, G., Deerinck, T. J., Ellisman, M. H., and Taylor, S. S. (1999) J. Cell Biol. 145, 951-959). In d-AKAP1a, translation may initiate from both Met-34 or Met-49 producing two molecules both targeted to mitochondria. The shorter molecule contains the 15-residue targeting motif, homologous to the N-terminal mitochondrial targeting motif of hexokinase I. Extensive mutagenesis showed that one hydrophobic surface of the 15-residue hexokinase-homologous segment contained the key elements for mitochondrial targeting. The same 15 residues are also part of the ER-targeting signal, but for ER targeting multiple hydrophobic residues are required that encompass both surfaces of the helix. The different involvement of the same helical motif for targeting to the two organelles appears to reflect different modes of interaction with the two organelles. This is the first example of a bifunctional helical element that is required for both ER and mitochondrion targeting.
Ma
Yuliang
Y
Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Taylor
Susan
S
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006593:Hexokinase / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C486333:Akap1 protein, mouse; D002352:Carrier Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D006593:Hexokinase; D017868:Cyclic AMP-Dependent Protein Kinases