The First Cytoplasmic Loop in the Core Structure of the ABCC1 (Multidrug Resistance Protein 1; MRP1) Transporter Contains Multiple Amino Acids Essential for Its Expression.
In: International journal of molecular sciences, Jg. 22 (2021-09-08), Heft 18
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Zugriff:
ABCC1 (human multidrug resistance protein 1 (hMRP1)) is an ATP-binding cassette transporter which effluxes xeno- and endobiotic organic anions and confers multidrug resistance through active drug efflux. The 17 transmembrane α-helices of hMRP1 are distributed among three membrane spanning domains (MSD0, 1, 2) with MSD1,2 each followed by a nucleotide binding domain to form the 4-domain core structure. Eight conserved residues in the first cytoplasmic loop (CL4) of MSD1 in the descending α-helix (Gly 392 , Tyr 404 , Arg 405 ), the perpendicular coupling helix (Asn 412 , Arg 415 , Lys 416 ), and the ascending α-helix (Glu 422 , Phe 434 ) were targeted for mutagenesis. Mutants with both alanine and same charge substitutions of the coupling helix residues were expressed in HEK cells at wild-type hMRP1 levels and their transport activity was only moderately compromised. In contrast, mutants of the flanking amino acids (G392I, Y404A, R405A/K, E422A/D, and F434Y) were very poorly expressed although Y404F, E422D, and F434A were readily expressed and transport competent. Modeling analyses indicated that Glu 422 and Arg 615 could form an ion pair that might stabilize transporter expression. However, this was not supported by exchange mutations E422R/R615E which failed to improve hMRP1 levels. Additional structures accompanied by rigorous biochemical validations are needed to better understand the bonding interactions crucial for stable hMRP1 expression.
Titel: |
The First Cytoplasmic Loop in the Core Structure of the ABCC1 (Multidrug Resistance Protein 1; MRP1) Transporter Contains Multiple Amino Acids Essential for Its Expression.
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Autor/in / Beteiligte Person: | Conseil, G ; Cole, SPC |
Zeitschrift: | International journal of molecular sciences, Jg. 22 (2021-09-08), Heft 18 |
Veröffentlichung: | Basel, Switzerland : MDPI, [2000-, 2021 |
Medientyp: | academicJournal |
ISSN: | 1422-0067 (electronic) |
DOI: | 10.3390/ijms22189710 |
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