RT Journal Article
T1 Functional characterization of MODY2 mutations in the nuclear export signal of glucokinase
A1 Gutierrez Nogués, Angel
A1 García Herrero, Carmen María
A1 Oriola, Josep
A1 Vincent, Olivier
A1 Navas, María Angeles
AB Glucokinase (GCK) plays a key role in glucose homeostasis. Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Besides its particular kinetic characteristics, glucokinase is regulated by subcellular compartmentation in hepatocytes. Glucokinase regulatory protein (GKRP) binds to GCK, leading to enzyme inhibition and import into the nucleus at fasting. When glucose concentration increases, GCK-GKRP dissociates and GCK is exported to the cytosol due to a nuclear export signal (NES). With the aim to characterize the GCK-NES, we have functionally analysed nine MODY2 mutations located within the NES sequence.Recombinant GCK mutants showed reduced catalytic activity and, in most cases, protein instability. Most of the mutants interact normally with GKRP, although mutations L306R and L309P impair GCK nuclear import in cotransfected cells. We demonstrated that GCK-NES function depends on exportin 1. We further showed that none of the mutations fully inactivate the NES, with the exception of mutation L304P, which likely destabilizes its α-helicoidal structure. Finally, we found that residue Glu300 negatively modulates the NES activity, whereas other residues have the opposite effect, thus suggesting that some of the NES spacer residues contribute to the low affinity of the NES for exportin 1, which is required for its proper functioning.In conclusion, our results have provided functional and structural insights regarding the GCK-NES and contributed to a better knowledge of the molecular mechanisms involved in the nucleo-cytoplasmic shuttling of glucokinase. Impairment of this regulatory mechanism by some MODY2 mutations might contribute to the hyperglycaemia in the patients.
PB Elsevier
SN 0925-4439
YR 2018
FD 2018
LK https://hdl.handle.net/20.500.14352/91408
UL https://hdl.handle.net/20.500.14352/91408
LA eng
NO Gutierrez-Nogués A, García-Herrero CM, Oriola J, Vincent O, Navas MA. Functional characterization of MODY2 mutations in the nuclear export signal of glucokinase. Biochim Biophys Acta Mol Basis Dis. 2018 Jul;1864(7):2385-2394.
NO Instituto de Salud Carlos III
DS Docta Complutense
RD 23 ene 2026