ABCB1 p.Leu443Arg
| Predicted by SNAP2: | A: D (59%), C: N (78%), D: D (75%), E: D (63%), F: N (97%), G: D (66%), H: D (59%), I: N (66%), K: D (71%), M: N (87%), N: D (53%), P: D (71%), Q: D (59%), R: D (66%), S: D (59%), T: D (53%), V: N (66%), W: D (53%), Y: N (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: N, Y: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] The Transmission Interfaces Contribute Asymmetrica... J Biol Chem. 2015 Jul 3;290(27):16954-63. doi: 10.1074/jbc.M115.652602. Epub 2015 May 18. Loo TW, Clarke DM
The Transmission Interfaces Contribute Asymmetrically to the Assembly and Activity of Human P-glycoprotein.
J Biol Chem. 2015 Jul 3;290(27):16954-63. doi: 10.1074/jbc.M115.652602. Epub 2015 May 18., [PMID:25987565]
Abstract [show]
P-glycoprotein (P-gp; ABCB1) is an ABC drug pump that protects us from toxic compounds. It is clinically important because it confers multidrug resistance. The homologous halves of P-gp each contain a transmembrane (TM) domain (TMD) with 6 TM segments followed by a nucleotide-binding domain (NBD). The drug- and ATP-binding sites reside at the interface between the TMDs and NBDs, respectively. Each NBD is connected to the TMDs by a transmission interface involving a pair of intracellular loops (ICLs) that form ball-and-socket joints. P-gp is different from CFTR (ABCC7) in that deleting NBD2 causes misprocessing of only P-gp. Therefore, NBD2 might be critical for stabilizing ICLs 2 and 3 that form a tetrahelix bundle at the NBD2 interface. Here we report that the NBD1 and NBD2 transmission interfaces in P-gp are asymmetric. Point mutations to 25 of 60 ICL2/ICL3 residues at the NBD2 transmission interface severely reduced P-gp assembly while changes to the equivalent residues in ICL1/ICL4 at the NBD1 interface had little effect. The hydrophobic nature at the transmission interfaces was also different. Mutation of Phe-1086 or Tyr-1087 to arginine at the NBD2 socket blocked activity or assembly while the equivalent mutations at the NBD1 socket had only modest effects. The results suggest that the NBD transmission interfaces are asymmetric. In contrast to the ICL2/3-NBD2 interface, the ICL1/4-NBD1 transmission interface is more hydrophilic and insensitive to mutations. Therefore the ICL2/3-NBD2 transmission interface forms a precise hydrophobic connection that acts as a linchpin for assembly and trafficking of P-gp.
Comments [show]
None has been submitted yet.
No. Sentence Comment
177 The amount of mature P-gp in mutants L443A, L443S, and L443F P-gps were similar to wild-type while mutant L443R yielded about 35% mature P-gp.
X
ABCB1 p.Leu443Arg 25987565:177:106
status: NEW192 Asymmetry of the P-gp Drug Pump Transmission Interfaces 16958 JOURNAL OF BIOLOGICAL CHEMISTRY VOLUME 290ߦNUMBER 27ߦJULY 3, 2015 blocked verapamil stimulated ATPase activity, the L443A mutant resembled wild-type activity, and the L443R mutant retained about 35% activity (Fig. 4B).
X
ABCB1 p.Leu443Arg 25987565:192:242
status: NEW212 The L443R and Y444R mutations only showed modest reductions (Fig. 4).
X
ABCB1 p.Leu443Arg 25987565:212:4
status: NEW276 The F1086R or Y1087R mutations at the NBD2 socket blocked maturation and activity while P-gp showed substantial activity when the comparable mutations (L443R, Y444R) were made to the NBD1 socket.
X
ABCB1 p.Leu443Arg 25987565:276:152
status: NEW