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Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.

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Gloyn, Anna L Odili, Stella Zelent, Dorothy Buettger, Carol Castleden, Harriet A J Van Schaftingen, Emile [UCL] Veiga da Cunha, Maria [UCL] Matschinsky, Franz M

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mM). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val62 has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of beta-cells and hepatocytes.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2005
Journal information "The Journal of biological chemistry" - Vol. 280, no. 14, p. 14105-13 (2005)
Peer reviewed yes
issn 0021-9258
Publication status Publié
Affiliation UCL - MD/BICL - Département de biochimie et de biologie cellulaire
MESH Subject Adaptor Proteins, Signal Transducing ; Animals ; Binding Sites ; Carrier Proteins - metabolism ; Child ; DNA Mutational Analysis ; Diabetes Mellitus, Type 2 - genetics ; Enzyme Activation ; Enzyme Stability ; Female ; Glucokinase - genetics - metabolism ; Glucose - metabolism ; Humans ; Hyperglycemia - genetics - metabolism ; Infant, Newborn ; Male ; Models, Molecular ; Pedigree ; Point Mutation ; Pregnancy ; Protein Structure, Tertiary ; Recombinant Fusion Proteins - genetics - metabolism ; Recombinant Proteins - genetics - metabolism
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Bibliographic reference Gloyn, Anna L ; Odili, Stella ; Zelent, Dorothy ; Buettger, Carol ; Castleden, Harriet A J ; et. al. Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young.. In: The Journal of biological chemistry, Vol. 280, no. 14, p. 14105-13 (2005)
Permanent URL http://hdl.handle.net/2078.1/25865