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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Philpot, R. M. Larson, J. R. Coon, M. J. Pernecky, S. J. |
| Description | Author Affiliation: Pernecky SJ ( Department of Biological Chemistry, Medical School, University of Michigan, Ann Arbor 48109.); |
| Abstract | The currently accepted model for the membrane topology of microsomal cytochrome P450 is that of a largely cytoplasmic domain bound by only one or two transmembrane segments at the NH2 terminus. However, as we have reported previously, P450 2E1 lacking the hydrophobic NH2-terminal signal peptide, like the full-length protein, is located in the inner cell membrane when expressed in Escherichia coli and is active with typical substrates. In the present study, additional variants of alcohol-inducible P450 2E1 as well as truncated forms of phenobarbital-inducible P450 2B4 were similarly expressed to determine the influence of the NH2-terminal region on the membrane-binding properties. After deletion of S1 (the NH2-terminal hydrophobic segment), or both S1 and L1 (the following hydrophilic region, expected to be lumenal or cytosolic), one-third of the resulting P450 2B4 (delta 2-20) and 2B4 (delta 2-27) remained membrane bound. Furthermore, the idea that the first two hydrophobic segments are required for attachment by a hairpin loop is not supported by the finding that after deletion of the S1, L1, and S2 segments about half of the P450 2E1 (delta 3-48) remained membrane bound. Since Na2CO3 treatment of the membrane fraction had no significant effect, the findings are apparently not attributable to a loose attachment or occlusion of the truncated proteins. The replacement of neutral amino acids by positively charged residues in positions 3 and 8 of P450 2E1 (delta 3-29) changed the amount in the cytosol from 35% to 50%, and the deletion of residues 2-20 or 2-27 from P450 2B4, which resulted in positive charges occurring in the NH2-terminal region, changed the amount in the cytosol from 27% to 67%. We conclude that alterations in the NH2-terminal region can change the location of the cytochrome from largely membranous to largely cytosolic and that the first two hydrophobic segments are not uniquely involved in membrane attachment. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 7 |
| Volume Number | 90 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 1993-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Aryl Hydrocarbon Hydroxylases Cytochrome P-450 Enzyme System Genetics Escherichia Coli Liver Enzymology Microsomes, Liver Oxidoreductases, N-Demethylating Steroid Hydroxylases Amino Acid Sequence Animals Cell Membrane Cloning, Molecular Cytochrome P-450 CYP2E1 Biosynthesis Cytosol DNA Isolation & Purification Enzyme Induction Ethanol Pharmacology Genetic Variation Kinetics Drug Effects Molecular Sequence Data Mutagenesis, Site-Directed Oligodeoxyribonucleotides Phenobarbital Polymerase Chain Reaction Recombinant Proteins Restriction Mapping Sequence Deletion Research Support, U.S. Gov't, P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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