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The mitochondrial intermembrane loop region of rat carnitine palmitoyltransferase 1A is a major determinant of its malonyl-CoA sensitivity
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Borthwick, Karen, Jackson, Vicky N., Price, Nigel T. and Zammit, Victor A. (2006) The mitochondrial intermembrane loop region of rat carnitine palmitoyltransferase 1A is a major determinant of its malonyl-CoA sensitivity. JOURNAL OF BIOLOGICAL CHEMISTRY, 281 (44). pp. 32946-32952. doi:10.1074/jbc.M600843200 ISSN 0021-9258.
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Official URL: http://dx.doi.org/10.1074/jbc.M600843200
Abstract
Carnitine palmitoyltransferase (CPT) 1A adopts a polytopic conformation within the mitochondrial outer membrane, having both the N- and C-terminal segments on the cytosolic aspect of the membrane and a loop region connecting the two transmembrane (TM) segments protruding into the inter membrane space. In this study we demonstrate that the loop exerts major effects on the sensitivity of the enzyme to its inhibitor, malonyl-CoA. Insertion of a 16-residue spacer between the C-terminal part of the loop sequence (i.e. between residues 100 and 101) and TM2 (which is predicted to start at residue 102) increased the sensitivity to malonyl-CoA inhibition of the resultant mutant protein by more than 10-fold. By contrast, the same insertion made between TM1 and the loop had no effects on the kinetic properties of the enzyme, indicating that effects on the catalytic C-terminal segment were specifically induced by loop-TM2 interactions. Enhanced sensitivity was also observed in all mutants in which the native TM2-loop pairing was disrupted either by making chimeras in which the loops and TM2 segments of CPT 1A and CPT 1B were exchanged or by deleting successive 9-residue segments from the loop sequence. The data suggest that the sequence spanning the loop-TM2 boundary determines the disposition of this TM in the membrane so as to alter the conformation of the C-terminal segment and thus affect its interaction with malonyl-CoA.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Subjects: | Q Science > QD Chemistry | ||||
| Journal or Publication Title: | JOURNAL OF BIOLOGICAL CHEMISTRY | ||||
| Publisher: | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | ||||
| ISSN: | 0021-9258 | ||||
| Official Date: | 3 November 2006 | ||||
| Dates: |
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| Volume: | 281 | ||||
| Number: | 44 | ||||
| Number of Pages: | 7 | ||||
| Page Range: | pp. 32946-32952 | ||||
| DOI: | 10.1074/jbc.M600843200 | ||||
| Publication Status: | Published |
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