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A mutation (R826W) in nucleotide‐binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes
Author(s) -
de Wet Heidi,
Proks Peter,
Lafond Mathilde,
Aittoniemi Jussi,
Sansom Mark S P,
Flanagan Sarah E,
Pearson Ewan R,
Hattersley Andrew T,
Ashcroft Frances M
Publication year - 2008
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2008.71
Subject(s) - atp hydrolysis , mutation , cyclic nucleotide binding domain , nucleotide , biochemistry , walker motifs , atpase , sulfonylurea receptor , chemistry , biology , enzyme , protein subunit , gene
Activating mutations in the pore‐forming Kir6.2 ( KCNJ11 ) and regulatory sulphonylurea receptor SUR1 ( ABCC8 ) subunits of the K ATP channel are a common cause of transient neonatal diabetes mellitus (TNDM). We identified a new TNDM mutation (R826W) in the first nucleotide‐binding domain (NBD1) of SUR1. The mutation was found in a region that heterodimerizes with NBD2 to form catalytic site 2. Functional analysis showed that this mutation decreases MgATP hydrolysis by purified maltose‐binding protein MBP–NBD1 fusion proteins. Inhibition of ATP hydrolysis by MgADP or BeF was not changed. The results indicate that the ATPase cycle lingers in the post‐hydrolytic MgADP·P i ‐bound state, which is associated with channel activation. The extent of MgADP‐dependent activation of K ATP channel activity was unaffected by the R826W mutation, but the time course of deactivation was slowed. Channel inhibition by MgATP was reduced, leading to an increase in resting whole‐cell currents. In pancreatic beta cells, this would lead to less insulin secretion and thereby diabetes.