The ATPase activities of SUR2A and SUR2B are influenced by the C-terminal 42 amino acids

• Published in: The FEBS journal 2010-06, Vol.277 (12), p.2654-2662
• Main Authors: de Wet, Heidi, Fotinou, Constantina, Amad, Nawaz, Dreger, Matthias, Ashcroft, Frances M.
• Format: Article
• Language: English
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-464X.2010.07675.x

Unusually among ATP-Binding Cassette (ABC) proteins, the sulphonylurea receptor (SUR) acts as a channel regulator. ATP-sensitive potassium (K ATP ) channels are octameric complexes made up from 4 pore-forming Kir6.2 subunits and 4 regulatory SUR subunits. Two different genes encode SUR1 ( ABCC8 ) and SUR2 ( ABCC9 ), with the latter being differentially spliced to give SUR2A and SUR2B which differ only in their C-terminal 42 amino acids. K ATP channels containing these different SUR2 isoforms are differentially modulated by MgATP, with Kir6.2/SUR2B being activated more than Kir6.2/SUR2A. We show here that purified SUR2B has a lower ATPase activity and 10-fold lower K m for MgATP than SUR2A. Similarly, the isolated nucleotide-binding domain 2 (NBD2) of SUR2B was less active than that of SUR2A. We further found that the NBDs of SUR2B (but not SUR2A) interact and that the activity of full-length SUR cannot be predicted from that of either the isolated NBDs or NBD mixtures. Notably, deletion of the last 42 amino acids from SUR2-NBD2 resulted in ATPase activity resembling SUR2-NBD2A rather than SUR2-NBD2B: this might indicate that these amino acids are responsible for the lower ATPase activity of SUR2B and isolated SUR2-NBD2B. We suggest that the lower ATPase activity of SUR2B may result in an enhanced duration of the MgADP-bound state that leads to channel activation.