Journal
MOLECULAR AND CELLULAR ENDOCRINOLOGY
Volume 382, Issue 1, Pages 55-65Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2013.08.020
Keywords
Aggregation; Catalytic activity; Cellular protein degradation; GCK-MODY diabetes; Protein misfolding; Self-association
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Funding
- Heise Vest, Innovest
- Norwegian Research Council
- Novo Nordisk Foundation
- European Research Council
- K.G. Jebsen Foundation
- Nils Norman Foundation
- Norwegian Diabetes Association
- University of Bergen
- Meltzer Foundation
- National Program for Research in Functional Genomics (FUGE)
- NIH [RO1 DK67536]
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GCK-MODY, dominantly inherited mild hyperglycemia, is associated with more than 600 mutations in the glucokinase gene. Different molecular mechanisms have been shown to explain GCK-MODY. Here, we report a Pakistani family harboring the glucokinase mutation c.823C > T (p.R275C). The recombinant and in cellulo expressed mutant pancreatic enzyme revealed slightly increased enzyme activity (kat) and normal affinity for ct-D-glucose, and resistance to limited proteolysis by trypsin comparable with wildtype. When stably expressed in HEK293 cells and MIN6 13-cells (at different levels), the mutant protein appeared misfolded and unstable with a propensity to form dimers and aggregates. Its degradation rate was increased, involving the lysosomal and proteasomal quality control systems. On mutation, a hydrogen bond between the R275 side-chain and the carbonyl oxygen of D267 is broken, destabilizing the F260-L271 loop structure and the protein. This promotes the formation of dimers/aggregates and suggests that an increased cellular degradation is the molecular mechanism by which R275C causes GCK-MODY. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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