Louie RJ, et al. (2010) Functional Rescue of a Misfolded Eukaryotic ATP-binding Cassette Transporter by Domain Replacement. J Biol Chem 285(46):36225-34
Abstract: ATP-binding cassette (ABC) transporters are integral membrane proteins that couple ATP binding/hydrolysis with the transport of hydrophilic substrates across lipid barriers. Deletion of Phe670 in the first nucleotide-binding domain (NBD1) of the yeast ABC-transporter, Yor1p, perturbs inter-domain associations, reduces functionality, and hinders proper transport to the plasma membrane. Functionality of Yor1p-DeltaF was restored upon co-expression of a peptide containing wild-type NBD1. To gain insight into the biogenesis of this important class of proteins, we defined the requirements for this rescue. We show that a misfolding lesion in NBD1 of the full-length protein is a pre-requisite for functional rescue by exogenous NBD1, which is mediated by physical replacement of the dysfunctional domain by the soluble NBD1. This association does not restore trafficking of Yor1p-DeltaF but instead confers catalytic activity to the small population of Yor1p-DeltaF that escapes to the plasma membrane. An important coupling between the exogenous NBD1 and ICL4 within full-length aberrant Yor1p-DeltaF is required for functional rescue but not for the physical interaction between the two polypeptides. Together, our genetic and biochemical data reveal that it is possible to modulate activity of ABC-transporters by physically replacing dysfunctional domains.
|Status: Published||Type: Journal Article||PubMed ID: 20843810|
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