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The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus.
J Mol Biol. 2001 Jul 13; 310(3):635-58.JM

Abstract

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.

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Authors+Show Affiliations

Narayana N
Department of Biochemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA.
Hua Q
No affiliation info available
Weiss MA
No affiliation info available

MeSH

Amino Acid SequenceCircular DichroismCrystallography, X-RayDNA-Binding ProteinsDiabetes Mellitus, Type 2DimerizationGuanidineHepatocyte Nuclear Factor 1Hepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 1-betaLeucine ZippersModels, MolecularMolecular Sequence DataMutationMutation, MissenseNuclear Magnetic Resonance, BiomolecularNuclear ProteinsPliabilityPolymorphism, GeneticProtein DenaturationProtein Structure, SecondaryProtein Structure, TertiarySequence AlignmentSolutionsSpectrometry, FluorescenceStatic ElectricityTranscription Factors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11439029

Citation

Narayana, N, et al. "The Dimerization Domain of HNF-1alpha: Structure and Plasticity of an Intertwined Four-helix Bundle With Application to Diabetes Mellitus." Journal of Molecular Biology, vol. 310, no. 3, 2001, pp. 635-58.
Narayana N, Hua Q, Weiss MA. The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus. J Mol Biol. 2001;310(3):635-58.
Narayana, N., Hua, Q., & Weiss, M. A. (2001). The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus. Journal of Molecular Biology, 310(3), 635-58.
Narayana N, Hua Q, Weiss MA. The Dimerization Domain of HNF-1alpha: Structure and Plasticity of an Intertwined Four-helix Bundle With Application to Diabetes Mellitus. J Mol Biol. 2001 Jul 13;310(3):635-58. PubMed PMID: 11439029.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus. AU - Narayana,N, AU - Hua,Q, AU - Weiss,M A, PY - 2001/7/6/pubmed PY - 2001/8/10/medline PY - 2001/7/6/entrez SP - 635 EP - 58 JF - Journal of molecular biology JO - J Mol Biol VL - 310 IS - 3 N2 - 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. SN - 0022-2836 UR - https://www.unboundmedicine.com/medline/citation/11439029/The_dimerization_domain_of_HNF_1alpha:_structure_and_plasticity_of_an_intertwined_four_helix_bundle_with_application_to_diabetes_mellitus_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022283601947801 DB - PRIME DP - Unbound Medicine ER -