Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria: The concept of chimeric signals

FEBS Journal

Volumn 278, Issue 22, 2011, Pages 4218-4229

  Avadhani, Narayan G ^a   Sangar, Michelle C ^a   Bansal, Seema ^a   Bajpai, Prachi ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

chimeric signals; cytochrome P450; mitochondrial targeting; multiple subcellular localization; protease processing; protein phosphorylation

Indexed keywords

CHOLESTANETRIOL 26 MONOOXYGENASE; CYTOCHROME; CYTOCHROME P450; CYTOCHROME P450 11A; CYTOCHROME P450 11B; CYTOCHROME P450 1A1; CYTOCHROME P450 24A; CYTOCHROME P450 27A; CYTOCHROME P450 2B1; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; MEMBRANE PROTEIN; TRANSPORTER OF THE OUTER MEMBRANE 20 PROTEIN; TRANSPORTER OF THE OUTER MEMBRANE 22 PROTEIN; TRANSPORTER OF THE OUTER MEMBRANE 70 PROTEIN; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; CELLULAR DISTRIBUTION; CHIMERA; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; MITOCHONDRIAL MEMBRANE; NONHUMAN; PRIORITY JOURNAL; PROTEIN CLEAVAGE; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; PROTEIN TRANSPORT; REVIEW; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION; STEADY STATE;

AMINO ACID SEQUENCE; ANIMALS; CYTOCHROME P-450 ENZYME SYSTEM; ENDOPLASMIC RETICULUM; HUMANS; MITOCHONDRIA; MOLECULAR SEQUENCE DATA; PROTEIN TRANSPORT; SEQUENCE HOMOLOGY, AMINO ACID; SIGNAL TRANSDUCTION;

EID: 80255136273     PISSN: 1742464X     EISSN: 17424658     Source Type: Journal    
DOI: 10.1111/j.1742-4658.2011.08356.x     Document Type: Review

References (88)

1. Blobel G, &, Sabatini DD, (1971) Ribosome-membrane interaction in eukaryotic cells. In Biomembranes (, Manson LA, ed), pp. 193-195. Plenum, New York.
2. Blobel G, (2000) Protein targeting. Biosci Rep 20, 303-344. (Pubitemid 32280911)
3. Anderson DJ, Walter P, &, Blobel G, (1982) Signal recognition protein is required for the integration of acetylcholine receptor d subunit. A transmembrane glycoprotein, into the endoplasmic reticulum membrane. J Cell Biol 93, 501-506. (Pubitemid 12014139)
4. Blobel G, &, Dobberstein B, (1975) Transfer of proteins across the membrane. I presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. J Cell Biol 67, 835-851.
5. Walter P, &, Johnson AE, (1994) Signal sequence recognition and protein targeting to the endoplasmic reticulum membrane. Ann Rev Cell Biol 10, 87-119. (Pubitemid 24372817)
6. Isenman L, Liebow C, &, Rothman S, (1995) Transport of proteins across membranes-a paradigm in transition. Biochim Biophys Acta 1241, 341-370. (Pubitemid 3018907)
7. Walter P, Ibrahimi I, &, Blobel G, (1981) Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein. J Cell Biol 91, 545-550. (Pubitemid 12215642)
8. Gould SJ, Keller GA, &, Subramani S, (1987) Identification of a peroxisome targeting signal at the carboxy terminus of firefly luciferase. J Cell Biol 105, 2923-2931. (Pubitemid 18043870)
9. Swinkels BW, Gould SJ, Bodnar AG, Rachubinski RA, &, Subramani S, (1991) A novel, cleavable peroxisomal targeting signal at the amino-terminus of the rat 3- ketoacyl-CoA thiolase. EMBO J 10, 3255-3262. (Pubitemid 21905350)
10. Kosugi S, Hasebe M, Matsumura N, Takashima H, Miyamoto-Sato E, Tomita M, &, Yanagawa H, (2009) Six classes of nuclear localization signals specific to different binding grooves of importin alpha. J Biol Chem 284, 478-485.
11. Fontes MR, The T, Jans D, Brinkworth RI, &, Kobe B, (2003) Structural basis for the specificity of bipartite nuclear localization sequence binding by importin-alpha. J Biol Chem 278, 27981-27987. (Pubitemid 36899993)
12. Wolf J, Schliebs W, &, Erdmann R, (2010) Peroxisomes as dynamic organelles: peroxisomal matrix protein import. FEBS J 277, 3268-3278.
13. Roise D, Theiler F, Horvath SJ, Tomich JM, Richards JH, Allison DS, &, Schatz G, (1988) Amphiphilicity is essential for mitochondrial presequence function. EMBO J 7, 649-653.
14. Hahne K, Haucke V, Ramage L, &, Schatz G, (1994) Incomplete arrest in the outer membrane sorts NADH-cytochrome b5 reductase to two different submitochondrial compartments. Cell 79, 829-839. (Pubitemid 24371973)
15. Lemire BD, Fankhauser C, Baker A, &, Schatz G, (1989) The mitochondrial targeting function of randomly generated peptide sequences correlates with predicted helical amphiphilicity. J Biol Chem 264, 20206-20215. (Pubitemid 20009197)
16. Folsch H, Guiard B, Neupert W, &, Stuart RA, (1996) Internal targeting signal of the BCS1 protein: a novel mechanism of import into mitochondria. EMBO J 15, 479-487. (Pubitemid 26044561)
17. Glick B, &, Schatz G, (1991) Import of proteins into mitochondria. Annu Rev Genet 25, 21-44. (Pubitemid 21903713)
18. Eilers M, &, Schatz G, (1986) Binding of a specific ligand inhibits import of a purified precursor protein into mitochondria. Nature 322, 228-232. (Pubitemid 16059446)
19. Yogev O, Naamati A, &, Pines O,. Fumarase: a paradigm of dual targeting and dual localized functions. FEBS J 278, 4230-4242.
20. Vongsamphanh R, Fortier PK, &, Ramotar D, (2001) Pir1p mediates translocation of the yeast Apn1p endonuclease into the mitochondria to maintain genomic stability. Mol Cell Biol 21, 1647-1655. (Pubitemid 32156384)
21. Prabu SK, Anandatheerthavarada HK, Raza H, Srinivasan S, Spear JF, &, Avadhani NG, (2006) Protein kinase A-mediated phosphorylation modulates cytochrome c oxidase function and augments hypoxia and myocardial ischemia-related injury. J Biol Chem 281, 2061-2070. (Pubitemid 43845794)
22. Raza H,. Dual localization of glutathione S-transferase in the cytosol and mitochondria: implications in oxidative stress, toxicity and disease. FEBS J 278, 4243-4251.
23. Haucke V, Ocana CS, Honlinger A, Tokatlidis K, Pfanner N, &, Schatz G, (1997) Analysis of the sorting signals directing NADH-cytochrome b5 reductase to two locations within yeast mitochondria. Mol Cell Biol 17, 4024-4032. (Pubitemid 27281878)
24. Sangar MC, Bansal S, &, Avadhani NG, (2010) Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity. Expert Opin Drug Metab Toxicol 6, 1231-1251.
25. Anandatheerthavarada HK, Biswas G, Robin MA, &, Avadhani NG, (2003) Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J Cell Biol 161, 41-54. (Pubitemid 36459078)
26. Devi L, Raghavendran V, Prabhu BM, Avadhani NG, &, Anandatheerthavarada HK, (2008) Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283, 9089-9100.
27. Wang HG, Rapp UR, &, Reed JC, (1996) Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 87, 629-638. (Pubitemid 26386937)
28. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, et al. (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323, 793-797.
29. Carrie C, Giraud E, Duncan O, Xu L, Wang Y, Huang S, Clifton R, Murcha M, Filipovska A, Rackham O, et al. (2010) Conserved an dnovel functions for Arabidopsis thaliana MIA40 in assembly of proteins in mitochondria and peroxisomes. J Biol Chem 285, 36138-36148.
30. Petrova VY, Drescher D, Kujumdzieva AV, &, Schmitt MJ, (2004) Dual targeting of yeast catalase A to peroxiomes and mitochondria. Biochem J 380, 393-400. (Pubitemid 38788110)
31. Lewin TM, Van Horn CG, Krisans SK, &, Coleman RA, (2002) Rat liver acyl CoA sythetase 4 is a peripheral-membrane protein located in two distinct subcellular organelles, peroxisomes, and mitochondrial-associated membrane. Arch Biochem Biophys 410, 263-270. (Pubitemid 34913557)
32. Adams JM, &, Cory S, (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322-1326. (Pubitemid 28406819)
33. Marchenko ND, Zaika A, &, Moll UM, (2000) Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem 275, 16202-16212. (Pubitemid 30366932)
34. Yang Sh, Liu R, Perez EJ, Wen Y, Stevens SM, Valencia T, Brun-Zinkernagel AM, Prokai L, Will Y, Dykens J, et al. (2004) Mitochondrial localization of estrogen receptor β. PNAS 101, 4130-4135.
35. Rane NS, Chakrabarti O, Feigenbaum L, &, Hegde RS, (2010) Signal sequence insufficiency contributes to neurodegeneration caused by transmembrane prion protein. J Cell Biol 188, 515-526.
36. Prokisch H, Andreoli C, Ahting U, Heiss K, Ruepp A, Scharfe C, &, Meitinger T, (2006) MitoP2: the mitochondrial proteome database-now including mouse data. Nucleic Acids Res 34, D705-D711.
37. Dinur M, Tal M, &, Pines O, (2008) Dual targeted mitochondrial proteins are characterized by lower MTS parameters and total net charge. PLoS ONE 2161, 1-8.
38. Raza H, &, Avadhani NG, (1988) Hepatic mitochondrial cytochrome P-450 system. Purification and characterization of two distinct forms of mitochondrial cytochrome P-450 from beta-naphthoflavone-induced rat liver. J Biol Chem 263, 9533-9541.
39. Shayiq RM, Addya S, &, Avadhani NG, (1991) Constitutive and inducible forms of cytochrome P450 from hepatic mitochondria. Methods Enzymol 206, 587-594.
40. Anandatheerthavarada HK, Addya S, Dwivedi RS, Biswas G, Mullick J, &, Avadhani NG, (1997) Localization of multiple forms of inducible cytochromes P450 in rat liver mitochondria: immunological characteristics and patterns of xenobiotic substrate metabolism. Arch Biochem Biophys 339, 136-150. (Pubitemid 27199763)
41. Addya S, Anandatheerthavarada HK, Biswas G, Bhagwat SV, Mullick J, &, Avadhani NG, (1997) Targeting of NH2-terminal-processed microsomal protein to mitochondria: a novel pathway for the biogenesis of hepatic mitochondrial P450MT2. J Cell Biol 139, 589-599. (Pubitemid 27485826)
42. Dasari VR, Anandatheerthavarada HK, Robin MA, Boopathi E, Biswas G, Fang JK, Nebert DW, &, Avadhani NG, (2006) Role of protein kinase C-mediated protein phosphorylation in mitochondrial translocation of mouse CYP1A1, which contains a non-canonical targeting signal. J Biol Chem 281, 30834-30847. (Pubitemid 44582138)
43. Anandatheerthavarada HK, Biswas G, Mullick J, Sepuri NB, Otvos L, Pain D, &, Avadhani NG, (1999) Dual targeting of cytochrome P4502B1 to endoplasmic reticulum and mitochondria involves a novel signal activation by cyclic AMP-dependent phosphorylation at Ser128. EMBO J 18, 5494-5504. (Pubitemid 29486369)
44. Bhagwat SV, Mullick J, Raza H, &, Avadhani NG, (1999) Constitutive and inducible cytochromes P450 in rat lung mitochondria: xenobiotic induction, relative abundance, and catalytic properties. Toxicol Appl Pharmacol 156, 231-240. (Pubitemid 29222637)
45. Boopathi E, Anandatheerthavarada HK, Bhagwat SV, Biswas G, Fang JK, &, Avadhani NG, (2000) Accumulation of mitochondrial P450MT2, NH(2)-terminal truncated cytochrome P4501A1 in rat brain during chronic treatment with beta-naphthoflavone. A role in the metabolism of neuroactive drugs. J Biol Chem 275, 34415-34423.
46. Anandatheerthavarada HK, Vijayasarathy C, Bhagwat SV, Biswas G, Mullick J, &, Avadhani NG, (1999) Physiological role of the N-terminal processed P4501A1 targeted to mitochondria in erythromycin metabolism and reversal of erythromycin-mediated inhibition of mitochondrial protein synthesis. J Biol Chem 274, 6617-6625. (Pubitemid 29111080)
47. Sangar MC, Anandatheerthavarada HK, Tang W, Prabu SK, Martin MV, Dostalek M, Guengerich FP, &, Avadhani NG, (2009) Human liver mitochondrial cytochrome P450 2D6-individual variations and implications in drug metabolism. FEBS J 276, 3440-3453.
48. Sangar MC, Anandatheerthavarada HK, Martin MV, Guengerich FP, &, Avadhani NG, (2010) Identification of genetic variants of human cytochrome P450 2D6 with impaired mitochondrial targeting. Mol Genet Metab 99, 90-97.
49. Dong H, Dalton TP, Miller ML, Chen Y, Uno S, Shi Z, Shertzer HG, Bansal S, Avadhani NG, &, Nebert DW, (2009) Knock-in mouse lines expressing either mitochondrial or microsomal CYP1A1: differing responses to dietary benzo[a]pyrene as proof of principle. Mol Pharmacol 75, 555-567.
50. Genter MB, Clay CD, Dalton TP, Dong H, Nebert DW, &, Shertzer HG, (2006) Comparison of mouse hepatic mitochondrial versus microsomal cytochromes P450 following TCDD treatment. Biochem Biophys Res Commun 342, 1375-1381.
51. Robin MA, Anandatheerthavarada HK, Fang JK, Cudic M, Otvos L, &, Avadhani NG, (2001) Mitochondrial targeted cytochrome P450 2E1 (P450 MT5) contains an intact N terminus and requires mitochondrial specific electron transfer proteins for activity. J Biol Chem 276, 24680-24689.
52. Robin MA, Anandatheerthavarada HK, Biswas G, Sepuri NB, Gordon DM, Pain D, &, Avadhani NG, (2002) Bimodal targeting of microsomal CYP2E1 to mitochondria through activation of an N-terminal chimeric signal by cAMP-mediated phosphorylation. J Biol Chem 277, 40583-40593. (Pubitemid 35215638)
53. Robin MA, Sauvage I, Grandperret T, Descatoire V, Pessayre D, &, Fromenty B, (2005) Ethanol increases mitochondrial cytochrome P450 2E1 in mouse liver and rat hepatocytes. FEBS Lett 579, 6895-6902. (Pubitemid 41773706)
54. Bai J, &, Cederbaum AI, (2006) Cycloheximide protects HepG2 cells from serum withdrawal-induced apoptosis by decreasing p53 and phosphorylated p53 levels. J Pharmacol Exp Ther 319, 1435-1443.
55. Lieber CS, Cao Q, DeCarli LM, Leo MA, Mak KM, Ponomarenko A, Ren C, &, Wang X, (2007) Role of medium-chain triglycerides in the alcohol-mediated cytochrome P450 2E1 induction of mitochondria. Alcohol Clin Exp Res 31, 1660-1668. (Pubitemid 47390036)
56. Moon KH, Hood BL, Kim BJ, Hardwick JP, Conrads TP, Veenstra TD, &, Song BJ, (2006) Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats. Hepatology 44, 1218-1230. (Pubitemid 44748372)
57. Raza H, Prabu SK, Robin MA, &, Avadhani NG, (2004) Elevated mitochondrial cytochrome P450 2E1 and glutathione S-transferase A4-4 in streptozotocin-induced diabetic rats: tissue-specific variations and roles in oxidative stress. Diabetes 53, 185-194. (Pubitemid 38044714)
58. Schenkman JB, &, Grein H, (1993) Cytochrome P450. (Handbook of Exp Pharmacol) (, Schenkman J.B., and, Greim H,. Eds.), Vol. 105, pp. 3-14, Springer-Verlag, Berlin Heidelberg.
59. Gonzalez FJ, (1990) Molecular genetics of the P-450 superfamily. Pharmacol Ther 45, 1-38. (Pubitemid 20013675)
60. Omura T, (2006) Mitochondrial P450s. Chem Biol Interact 163, 86-93. (Pubitemid 44572220)
61. Werck-Reichhart D, &, Feyereisen R, (2000) Cytochromes P450: a success story. Genome Biol 1, 3003.1-3003.9.
62. Guengerich FP, (2001) Common and uncommon cytochrome P450 reactions related to toxicity. Chem Res Toxicol 14, 611-650. (Pubitemid 32565712)
63. Hunter AL, Cruz RP, Cheyne BM, McManus BM, &, Granville DJ, (2004) Cytochrome P-450 enzymes and cardiovascular diseases. Can J Physiol Pharmacol 82, 1053-1060. (Pubitemid 40343641)
64. Ding X, &, Kaminsky LS, (2003) Human extrahepatic metabolism and tissue selective, chemical toxicity in the respiratory and gastrointestinal tracts. Ann Rev Pharmacol Toxicol 43, 149-173. (Pubitemid 37372638)
65. Sakaguchi M, Mihara K, &, Sato R, (1984) Signal recognition particle is required for co-translational insertion of cytochrome P-450 into microsomal membranes. Proc Natl Acad Sci USA 81, 3361-3364. (Pubitemid 14122676)
66. Oliver J, Jungnickel B, Gorlich D, Rapoport T, &, High S, (1995) The Sec61 complex is essential for the insertion of proteins into the membrane of the endoplasmic reticulum. FEBS Lett 362, 126-130.
67. Bar-Nun S, Kreibich G, Adesnik M, Alterman L, Negishi M, &, Sabatini DD, (1980) Synthesis and insertion of cytochrome P-450 into endoplasmic reticulum membranes. Proc Natl Acad Sci USA 77, 965-969.
68. Monier S, Van Luc P, Kreibich G, Sabatini DD, &, Adesnik M, (1988) Signals for the incorporation and orientation of cytochrome P450 in the endoplasmic reticulum membrane. J Cell Biol 107, 457-470.
69. Szczesna-Skorupa E, &, Kemper B, (2008) Influence of protein-protein interactions on the cellular localization of cytochrome P450. Expert Opin Drug Metab Toxicol 4, 123-136. (Pubitemid 351308412)
70. Szczesna-Skorupa E, &, Kemper B, (2001) The juxtamembrane sequence of cytochrome P-450 2C1 contains an endoplasmic reticulum retention signal. J Biol Chem 276, 45009-45014.
71. Anandatheerthavarada HK, Sepuri NB, &, Avadhani NG, (2009) Mitochondrial targeting of cytochrome P450 proteins containing NH2-terminal chimeric signals involves an unusual TOM20/TOM22 bypass mechanism. J Biol Chem 284, 17352-17363.
72. Niranjan BG, Wilson NM, Jefcoate CR, &, Avadhani NG, (1984) Hepatic mitochondrial cytochrome P-450 system. Distinctive features of cytochrome P-450 involved in the activation of aflatoxin B1 and benzo(a)pyrene. J Biol Chem 259, 12495-12501. (Pubitemid 15203757)
73. Bhagwat SV, Biswas G, Anandatheerthavarada HK, Addya S, Pandak W, &, Avadhani NG, (1999) Dual targeting property of the N- terminal signal sequence of P4501A1. Targeting of heterologous proteins to endoplasmic reticulum and mitochondria. J Biol Chem 274, 24014-24022.
74. Boopathi E, Srinivasan S, Fang JK, &, Avadhani NG, (2008) Bimodal protein targeting through activation of cryptic mitochondrial targeting signals by an inducible cytosolic endoprotease. Mol Cell 32, 32-42.
75. Knockaert L, Fromenty B, &, Robin MA, (2011) Mechanism of mitochondrial targeting of cytochrome P450 2E1: physiopathological role in liver injur and obesity. FEBS J 278, 4252-4260.
76. Bird P, Gething MJ, &, Sambrook J, (1990) The functional efficiency of a mammalian signal peptide is directly related to its hydrophobicity. J Biol Chem 265, 8420-8425.
77. Ng DT, Brown JD, &, Walter P, (1996) Signal sequences specify the targeting route to the endoplasmic reticulum membrane. J Cell Biol 134, 269-278. (Pubitemid 26250697)
78. Bansal S, Liu CP, Sepuri NB, Anandatheerthavarada HK, Selvaraj V, Hoek J, Milne GL, Guengerich FP, &, Avadhani NG, (2010) Mitochondria targeted CYP 2E1 induces oxidative damage and augments alcohol mediated oxidative stress. J Biol Chem 285, 24609-24619.
79. Ellis RJ, (2003) Molecular chaperones: plugging the transport gap. Nature 421, 801-802. (Pubitemid 36254129)
80. Ren J, Bharti A, Raina D, Chen W, Ahmad R, &, Kufe D, (2006) MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene 25, 20-317.
81. Voos W, (2003) A new connection: chaperones meet a mitochondrial receptor. Mol Cell 11, 1-3. (Pubitemid 36126582)
82. Anandatheerthavarada HK, Amuthan G, Biswas G, Robin MA, Murali R, Waterman MR, &, Avadhani NG, (2001) Evolutionarily divergent electron donor proteins interact with P450MT2 through the same helical domain but different contact points. EMBO J 20, 2394-2403. (Pubitemid 32452857)
83. Zangar RC, Davydov DR, &, Verma S, (2004) Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol Appl Pharmacol 199, 316-331. (Pubitemid 39208731)
84. Guengerich FP, (2006) Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS J 8, E101-E111.
85. Harrelson WG Jr, &, Mason RP, (1982) Microsomal reduction of gentian violet. Evidence for cytochrome P-450-catalyzed free radical formation. Mol Pharmacol 22, 239-242. (Pubitemid 12028818)
86. Bhagwat SV, Boyd MR, &, Ravindranath V, (2000) Multiple forms of cytochrome P450 and associated monooxygenase activities in human brain mitochondria. Biochem Pharmacol 59, 573-582. (Pubitemid 30045595)
87. Neve EP, &, Ingelman-Sundberg M, (1999) A soluble NH(2)-terminally truncated catalyticallyactive form of rat cytochrome P450 2E1 targeted to liver mitochondria. FEBS Lett 460, 309-314. (Pubitemid 29495960)
88. Dutheil F, Dauchy S, Diry M, Sazdovitch V, Cloarec O, Mellottée L, Bièche I, Ingelman-Sundberg M, Flinois JP, de Waziers I, et al. (2009) Xenobiotic-metabolizing enzymes and transporters in the normal human brain: regional and cellular mapping as a basis for putative roles in cerebral function. Drug Metab Dispos 37, 1528-1538.