Intramolecular Interaction of SUR2 Subtypes for Intracellular ADP-Induced Differential Control of K _ATP Channels

Abstract

Abstract-ATP-sensitive K ϩ (K ATP ) channels are composed of sulfonylurea receptors (SURs) and inwardly rectifying Kir6.2-channels. The C-terminal 42 amino acid residues (C42) of SURs are responsible for ADP-induced differential activation of K ATP channels in SUR-subtypes. By examining ADP-effect on K ATP channels containing various chimeras of SUR2A and SUR2B, we identified a segment of 7 residues at central portion of C42 critical for this phenomenon. A 3-D structure model of the region containing the second nucleotide-binding domain (NBD2) of SUR and C42 was developed based on the structure of HisP, a nucleotide-binding protein forming the bacterial Histidine transporter complex. In the model, the polar and charged residues in the critical segment located within a distance that allows their electrostatic interaction with Arg1344 at the Walker-A loop of NBD2. Therefore, the interaction might be involved in the control of ADP-induced differential activation of SUR2-subtype K ATP channels. A TP-sensitive K ϩ (K ATP ) channels are inhibited by intracellular ATP and activated by nucleoside diphosphates and thus provide a link between the metabolic state and cellular excitability in various organs, including pancreas, heart, vasculature, and brain. 1 These channels are associated with such cellular functions as insulin secretion, cardiac preconditioning, vasodilatation, and neurotransmitter release. K ATP channels are heterooctamers composed of an ATPbinding cassette protein, known as the sulfonylurea receptor (SUR), and an inwardly rectifying K ϩ channel (Kir) subunit, Kir6.0. 2,3 Three kinds of SUR, SUR1, SUR2A, and SUR2B, have been isolated and their roles in formation of functional K ϩ channels with Kir6.0 subunits have been extensively examined. [2][3][4][5][6] It is now widely accepted that SUR1, SUR2A, and SUR2B represent pancreatic, cardiac, and vascular smooth muscle types of SUR, respectively. When expressed with Kir6.2, all 3 subtypes of SUR form K ATP channels that exhibit the same single-channel characteristics; weak inwardrectification and a unitary conductance of Ϸ80 pS in the inward-direction with 150 mmol/L extracellular K ϩ . They, however, show distinct sensitivities to different vasorelaxant K ϩ channel opener compounds (KCOs), intracellular MgADP, and sulfonylurea drug derivatives. [7][8][9][10][11] The different pharmacological sensitivities depend on the SUR-subtype. SUR has been assigned to the ATP-binding-cassette (ABC) superfamily, as is assumed to possess 17 transmembrane segments and 2 nucleotide-binding domains (NBDs) with Walker-A and -B consensus motifs for binding intracellular nucleotides. 12,13 However, structural elements of SURs and their functional roles responsible for their different features have not been fully determined.The majority of ABC proteins are active transporters, utilizing the energy of ATP hydrolysis to pump solutes and small substances across the membrane. SUR on the other hand regulates the behavior of Kir6.0 channel pores, and thus, the role of the 2 NBDs dif...

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

“…Structural characteristics of SUR2A suggest specialized domains that particularly influence the ATPase cycle and associated nucleotide-dependent K ATP channel gating [57]. A high resolution three-dimensional model of SUR2A NBD2, obtained with 1 fs time step molecular dynamics simulation, identifies a β-strand, within the SUR tissue-specific carboxy-terminal tail, that may interact with the Walker A motif due to the spatial geometry of the folded molecule [14].…”

“…This finding underscores that SUR-mediated gating of the channel pore depends not only upon nucleotide binding to NBDs as classically proposed, but also on the predominant conformational intermediate adopted by the intrinsic ATPase cycle. Furthermore, differences in the pattern of probabilities and lifetimes of individual SUR conformations, in addition to distinct ATPase rates, may contribute to the tissue-specificity of nucleotide-dependent K ATP channel regulation [57,58].…”

ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating

“…Structural molecular dynamics simulation showed that the residues Ala1513 and Leu1524 flank the Cterminal β-strand in close proximity to the signature Walker A motif (Fig. 2c,d), required for coordination of nucleotides in the catalytic pocket of ATP-binding cassette proteins 21,22 . Replacement of Ala1513 with a sterically larger and more hydrophilic threonine residue or truncation of the C terminus caused by the Fs1524 mutation would .…”

Functional Role of C-Terminal Sequence Elements in the Transporter Associated with Antigen Processing

“…The distinct nucleotide binding and function of the TAP-NBDs are mediated by the nonhomologous C-terminal tails of the two TAP chains and not by the core NBDs containing the conserved sequence motifs of the ATP-binding cassette (11). The functional importance of the C-terminal tails of the NBDs has been shown for several different members of the ABC transporter family (12)(13)(14)(15)(16). For example, the P-glycoprotein (12) can only tolerate small C-terminal deletions.…”

“…For example, the P-glycoprotein (12) can only tolerate small C-terminal deletions. In addition, results reported for the ABC protein sulfonylurea receptor (SUR) suggest that residues in the ␤ 11 strand of the C-terminal tail control the nucleotide-binding and catalytic functions of the NBD2 (16). Most interestingly, four different splicing isoforms of the TAP-related ABC half-transporter TAPL have recently been reported with heterogeneity of the C-terminal region, suggesting that the function of this ABC transporter may be modulated by the C-terminal tail (17).…”