Fig. 1: HNF1A H126D mutation alters amino acid interactions and HNF1A protein conformation. | Nature Communications

Fig. 1: HNF1A H126D mutation alters amino acid interactions and HNF1A protein conformation.

From: Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells

Fig. 1

a MODY3 family pedigree. Square denotes male, circles denote females. Solid circles denote diabetic individuals. BMI body mass index, HbA1c haemoglobin A1c. b HNF1A gene structure consists of three functional domains: dimerization domain (red), DNA-binding domain (blue) and transactivation domain (orange). H126D mutation occurs in the DNA-binding domain. c Multiple sequence alignment of HNF1A protein sequences amongst various species. H126 is highlighted in red box. d Structures of WT HNF1A (PDB 1IC8) and H126D mutant protein (green and cyan) bound to a gene promoter. Interactions between H126/D126 and E172 are highlighted in red circles. e Computed binding free energies (∆H) for formation of protein–DNA complexes for WT HNF1A and H126D mutant (entropy change was assumed to be the same for all complexes and therefore ignored). f Histogram of intramolecular hydrogen bond counts obtained from conventional molecular dynamics (cMD) simulations of WT (black) and mutant HNF1A H126D (blue) complexed with DNA, and accelerated molecular dynamics (aMD) simulations of H126D mutant HNF1A complexed with DNA (unweighted, red). A hydrogen bond is counted when the angle between the donor and acceptor heavy atoms is greater than or equal to 135° and their distance is less than or equal to 3.5 Å. g Representative trajectory structures obtained from the cMD simulations of WT and mutant H126D HNF1A. The insets (highlighted in red circles) show the interactions of H126 and D126 with neighboring residues. WT wild-type, P1 patient 1, P2 patient 2. “See also Supplementary Movies 1 and 2, and Fig. S1.” Source data are provided as a Source data file.

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