Membrane topology of the N-terminal half of the hamster P-glycoprotein molecule

Jian-Ting Zhang, M. Duthie, V. Ling

Research output: Contribution to journalArticle

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Abstract

P-glycoprotein (Pgp) is a tandemly duplicated plasma membrane protein containing 12 predicted transmembrane (TM) segments and two cytoplasmic ATP- binding domains. Pgp appears to be responsible for multidrug resistance in cancer cells. A detailed knowledge of the topological structure of Pgp will be required for understanding its mechanism of action. Previously, we have investigated the membrane orientation of Pgp using a cell free translation/translocation system supplemented with canine pancreatic microsomal membranes. We observed unexpectedly that the C-terminal half of the Pgp molecules was present in two different topological orientations (Zhang, J.-T., and Ling, V. (1991) J. Biol. Chem. 266, 18224-18232). In the present study, using a similar approach, we have investigated in detail the topological structure of the N-terminal half of the Pgp molecule. Again, two orientations were observed. One has all six predicted TM segments in the membrane bilayer, the other has only four TM segments in the bilayer with predicted TM3 and TM5 in a cytoplasmic and extracellular location, respectively. Although the primary sequence of Pgp appears to be a tandem duplication, the new topological structure of N-terminal half is not a simple tandem duplication of that in the C-terminal half. Thus it appears that the insertion and orientation of Pgp TM segments are dictated by specific localized sequences. These results, together with our previous findings, raise the possibility that Pgp in the native membrane may be present in different topological orientations and this feature may be important for its function.

Original languageEnglish (US)
Pages (from-to)15101-15110
Number of pages10
JournalJournal of Biological Chemistry
Volume268
Issue number20
StatePublished - 1993
Externally publishedYes

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P-Glycoprotein
Cricetinae
Topology
Membranes
Molecules
Multiple Drug Resistance
Cell membranes
Canidae
Blood Proteins
Membrane Proteins
Adenosine Triphosphate
Cells
Cell Membrane

ASJC Scopus subject areas

  • Biochemistry

Cite this

Membrane topology of the N-terminal half of the hamster P-glycoprotein molecule. / Zhang, Jian-Ting; Duthie, M.; Ling, V.

In: Journal of Biological Chemistry, Vol. 268, No. 20, 1993, p. 15101-15110.

Research output: Contribution to journalArticle

Zhang, J-T, Duthie, M & Ling, V 1993, 'Membrane topology of the N-terminal half of the hamster P-glycoprotein molecule', Journal of Biological Chemistry, vol. 268, no. 20, pp. 15101-15110.
Zhang, Jian-Ting ; Duthie, M. ; Ling, V. / Membrane topology of the N-terminal half of the hamster P-glycoprotein molecule. In: Journal of Biological Chemistry. 1993 ; Vol. 268, No. 20. pp. 15101-15110.
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