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Published 28 February 2005. doi:10.1083/jcb.200407082
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 5, 735-745
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Article

N-myristoylation determines dual targeting of mammalian NADH-cytochrome b(5) reductase to ER and mitochondrial outer membranes by a mechanism of kinetic partitioning



Sara Colombo1, Renato Longhi2, Stefano Alcaro3, Francesco Ortuso3, Teresa Sprocati1, Adriano Flora1, and Nica Borgese1,3

1 Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section and Department of Medical Pharmacology, University of Milan, 20129 Milan, Italy
2 Consiglio Nazionale delle Ricerche Institute of Chemistry of Molecular Recognition, 20133 Milan, Italy
3 Department of Pharmacobiology, University of Catanzaro, 88021 Roccelletta di Borgia (Catanzaro), Italy

Correspondence to Nica Borgese: n.borgese{at}in.cnr.it

Mammalian NADH-cytochrome b(5) reductase (b5R) is an N-myristoylated protein that is dually targeted to ER and mitochondrial outer membranes. The N-linked myristate is not required for anchorage to membranes because a stretch of hydrophobic amino acids close to the NH2 terminus guarantees a tight interaction of the protein with the phospholipid bilayer. Instead, the fatty acid is required for targeting of b5R to mitochondria because a nonmyristoylated mutant is exclusively localized to the ER. Here, we have investigated the mechanism by which N-linked myristate affects b5R targeting. We find that myristoylation interferes with interaction of the nascent chain with signal recognition particle, so that a portion of the nascent chains escapes from cotranslational integration into the ER and can be post-translationally targeted to the mitochondrial outer membrane. Thus, competition between two cotranslational events, binding of signal recognition particle and modification by N-myristoylation, determines the site of translation and the localization of b5R.

A. Flora's present address is Baylor College of Medicine, Houston, TX 77030.

Abbreviations used in this paper: b5R, NADH-cytochrome b(5) reductase; CD, circular dichroism; DPM, dog pancreas microsomes; DSS, disuccinimidylsuberate; GAPDH, glyceraldehyde phosphate dehydrogenase; MOM, mitochondrial outer membrane; MyrCoA, myristoyl-CoA; NMT, N-myristoyl-CoA:protein myristoyltransferase; RNC, ribosome-nascent chain complex; SRP, signal recognition particle; TFE, trifluoroethanol; wt, wild-type.


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