title: N-myristoylation determines dual targeting of mammalian NADH-cytochrome b5 reductase to ER and mitochondrial outer membranes by a mechanism of kinetic partitioning.
abstract: Mammalian NADH-cytochrome b5 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.
authors.affiliation: Consiglio Nazionale delle Ricerche Institute of Neuroscience, Cellular and Molecular Pharmacology Section and Department of Medical Pharmacology, University of Milan, 20129 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Colombo
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Teresa
authors.initials: T
authors.lastname: Sprocati
authors.forename: Adriano
authors.initials: A
authors.lastname: Flora
authors.forename: Nica
authors.initials: N
authors.lastname: Borgese
mesh_terms: D000818:Animals; D042966:Cytochrome-B(5) Reductase / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D019814:Myristic Acid / Q000378:metabolism*; D011487:Protein Conformation; D021381:Protein Transport / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018271:Signal Recognition Particle / Q000378:metabolism; D014162:Transfection
chemical_list: D012333:RNA, Messenger; D018271:Signal Recognition Particle; D019814:Myristic Acid; D042966:Cytochrome-B(5) Reductase
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