1jb6
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Crystal Structure of Dimerization Domain (1-33) of HNF-1alpha
OverviewOverview
Maturity-onset diabetes mellitus of the young (MODY) is a human genetic, syndrome most commonly due to mutations in hepatocyte nuclear, factor-1alpha (HNF-1alpha). Here, we describe the crystal structure of the, HNF-1alpha dimerization domain at 1.7 A resolution and assess its, structural plasticity. The crystal's low solvent content (23%, v/v) leads, to tight packing of peptides in the lattice. Two independent dimers, similar in structure, are formed in the unit cell by a 2-fold, crystallographic symmetry axis. The dimers define a novel intertwined, four-helix bundle (4HB). Each protomer contains two alpha-helices, separated by a sharp non-canonical turn. Dimer-related alpha-helices form, anti-parallel coiled-coils, including an N-terminal "mini-zipper", complementary in structure, symmetry and surface characteristics to, transcriptional coactivator dimerization cofactor of HNF-1 (DCoH). A, confluence of ten leucine side-chains (five per protomer) forms a, hydrophobic core. Isotope-assisted NMR studies demonstrate that a similar, intertwined dimer exists in solution. Comparison of structures obtained in, multiple independent crystal forms indicates that the mini-zipper is a, stable structural element, whereas the C-terminal alpha-helix can adopt a, broad range of orientations. Segmental alignment of the mini-zipper (mean, pairwise root-mean-square difference (rmsd) in C(alpha) coordinates of, 0.29 A) is associated with a 2.1 A mean C(alpha) rmsd displacement of the, C-terminal coiled-coil. The greatest C-terminal structural variation (4.1, A C(alpha) rmsd displacement) is observed in the DCoH-bound peptide., Diabetes-associated mutations perturb distinct structural features of the, HNF-1alpha domain. One mutation (L12H) destabilizes the domain but, preserves structural specificity. Adjoining H12 side-chains in a, native-like dimer are predicted to alter the functional surface of the, mini-zipper involved in DCoH recognition. The other mutation (G20R), by, contrast, leads to a dimeric molten globule, as indicated by its 1H-NMR, features and fluorescent binding of 1-anilino-8-naphthalene sulfonate. We, propose that a glycine-specific turn configuration enables specific, interactions between the mini-zipper and the C-terminal coiled-coil.
About this StructureAbout this Structure
1JB6 is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.
ReferenceReference
The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus., Narayana N, Hua Q, Weiss MA, J Mol Biol. 2001 Jul 13;310(3):635-58. PMID:11439029
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