Determinant of the extracellular location of the N-terminus of human multidrug-resistance-associated protein

Jian-Ting Zhang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Multidrug-resistance-associated protein (MRP) is a member of the ATP-binding cassette (ABC) membrane-transport superfamily and is responsible for multidrug resistance in cancer cells. Distinct from other members of the ABC superfamily, MRP has three membrane-spanning domains (MSDs) and the N-terminus is located extracellularly. It has been shown that the first MSD (MSD1) with an extracellular N-terminus is important for MRP function. To address what ensures the generation of this structural organization of MRP and to understand in general the molecular mechanism of membrane folding of polytopic proteins with extracellular N-termini, the biogenesis of MSD1 in human MRP1 was examined using an in vitro expression system. Surprisingly, the second transmembrane segment (TM2) in MSD1 was found to play a critical role in the correct membrane translocation and folding of MSD1 in human MRP1. TM2 not only plays an essential role to ensure the N-terminus-outside/ C-terminus-inside orientation of TM1 with an extracellular N-terminus, it can also translocate into membranes post-translationally in a signal-recognition particle and ribosome-dependent manner to provide an additional insurance for correct folding of MSD1 in MRP. These findings suggest that TM2 in a polytopic membrane protein. with an extracellular N-terminus may play a critical role in controlling correct membrane translocation and folding of the protein in general.

Original languageEnglish
Pages (from-to)597-606
Number of pages10
JournalBiochemical Journal
Volume348
Issue number3
DOIs
StatePublished - Jun 15 2000

Fingerprint

Multidrug Resistance-Associated Proteins
Membranes
Protein Folding
Adenosine Triphosphate
Signal Recognition Particle
Insurance
Multiple Drug Resistance
Protein Transport
Ribosomes
Membrane Proteins
Proteins
Cells

Keywords

  • Membrane targeting
  • MRP
  • Ribosome
  • Signal sequence
  • Topogenesis

ASJC Scopus subject areas

  • Biochemistry

Cite this

Determinant of the extracellular location of the N-terminus of human multidrug-resistance-associated protein. / Zhang, Jian-Ting.

In: Biochemical Journal, Vol. 348, No. 3, 15.06.2000, p. 597-606.

Research output: Contribution to journalArticle

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