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Reference: Pagant S, et al. (2010) Intragenic suppressing mutations correct the folding and intracellular traffic of misfolded mutants of yor1p, a eukaryotic drug transporter. J Biol Chem 285(47):36304-14

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Abstract


ATP-binding cassette (ABC) transporters play pivotal physiological roles in substrate transport across membranes, and defective assembly of these proteins can cause severe disease associated with improper drug or ion flux. The yeast protein Yor1p is a useful model to study the biogenesis of ABC transporters; deletion of a phenylalanine residue in the first nucleotide binding domain (NBD1) causes misassembly and retention in the endoplasmic reticulum (ER) of the resulting protein Yor1p- DeltaF670, similar to the predominant disease-causing allele in humans, CFTR- DeltaF508. Here we describe two novel Yor1p mutants, G278R and I1084P, which fail to assemble and traffic similar to Yor1p- DeltaF670. These mutations are located in the two intracellular loops (ICLs) that interface directly with NBD1, and thus disrupt a functionally important structural module. We isolated two second-site mutations, F270S and R1168M, that partially correct the folding injuries associated with the G278R, I1084P and DeltaF670 mutants and that reinstate their trafficking. The position of both corrective mutations at the cytoplasmic face of a transmembrane helix suggests that they restore biogenesis by influencing the behavior of the transmembrane domains rather than by direct restoration of the ICL1-ICL4-NBD1 structural module. Given the conserved topology of many ABC transporters, our findings provide new understanding of functionally important inter-domain interactions and suggest new potential avenues for correcting folding defects caused by abrogation of those domain interfaces.

Reference Type
Journal Article
Authors
Pagant S, Halliday JJ, Kougentakis C, Miller EA
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