Structural Basis of Disease-Causing Mutations in Hepatocyte Nuclear Factor 1β^,

Abstract

HNF1β is an atypical POU transcription factor that participates in a hierarchical network of transcription factors controlling the development and proper function of vital organs such as liver, pancreas, and kidney. Many inheritable mutations on HNF1β are the monogenic causes of diabetes and several kidney diseases. To elucidate the molecular mechanism of its function and the structural basis of mutations, we have determined the crystal structure of human HNF1β DNA binding domain in complex with a high-affinity promoter. Disease-causing mutations have been mapped to our structure, and their predicted effects have been tested by a set of biochemical/ functional studies. These findings together with earlier findings with a homologous protein HNF1α, help us to understand the structural basis of promoter recognition by these atypical POU transcription factors and the site-specific functional disruption by disease-causing mutations.HNF1β (hepatocyte nuclear factor 1β; also known as vHNF1 or TCF2) is a widely distributed transcription factor that plays a critical role in early vertebrate development and embryonic survival (1-3). First identified as a key regulator in the liver, HNF1β is also expressed in the pancreas, kidney, lung, ovary, testis, and throughout the gastrointestinal tract. In pancreatic β-cells, HNF1β is known to form an integrated regulatory network with other transcription factors such as HNF1α, HNF4α, Pdx-1, Foxa2, and NeuroD1 for organ development and proper function (1,4). Thus, in humans, heterozygous mutations in the HNF1β gene have been linked to neonatal diabetes (5) and the autosomal dominant subtype of diabetes known as MODY (maturity-onset diabetes of the young) (6). Extrapancreatic diseases are also increasingly recognized in different organs, especially in the kidney, with a variety of renal developmental disorders such as renal cysts, familial hypoplastic glomerulocystic kidney disease, renal malformation, and atypical familial hyperuricaemic nephropathy (7-11).POU transcription factors, which include Pit-1, Oct-1, and Unc-86 as founding members and are now expanded to more than 13 members in humans, are developmental regulators of various neuroendocrine organs, and their sequence-specific DNA binding is mediated by a bipartite motif that consists of a POU homeodomain (POU H ) and POU-specific domain (POU S ) (12,13). POU H is a 60 amino acid classic homeodomain made of three α-helices with the third as a DNA recognition helix, while POU S is an additional ∼75 amino acid all-α-helical motif that cooperates with POU H to enhance the binding affinity and specificity of DNA binding ( Figures 1 and 2) (12,14). HNF1α (MODY3 gene product, the most commonly mutated MODY protein) and HNF1β (MODY5 gene product) are atypical members of the POU transcription factors. Their POU S domains have at least one additional α-helix at the N-terminus, and the second † This work was funded by the Juvenile Diabetes Research Foundation (1-2004-506) (8,24). Recently, HNF1β has also been associated wi...

Structural Basis of Natural Promoter Recognition by a Unique Nuclear Receptor, HNF4α

“…Only 1 of 17 DNA contacting residues (Arg 125 at the downstream half-site but not at the upstream half-site) is mutated in MODY1 patients (Figs. 2, C and D), which is in contrast to related MODY gene products, such as HNF1␣ (MODY3) and HNF1␤ (MODY5), in which numerous loss-offunction mutations are found on residues involved in DNA binding or protein core packing (66,67). Consistent with these findings, all of the known mutations cause only modest reductions in overall transcriptional activity, with the greatest reduction being slightly over 50% as a result of the G115S mutation (Fig.…”

Specification of hepatopancreas progenitors in zebrafish by hnf1ba and wnt2bb

“…1K), is predicted to be involved in the formation of the POU-specific domain hydrophobic core but not make direct contact with DNA (supplementary material Fig. S1A) (Lu et al, 2007). Therefore, substitution of a highly charged group (V147E) is predicted to perturb the hydrophobic core and disrupt protein structure and function.…”

HNF1B-associated clinical phenotypes: the kidney and beyond

“…hgnc_id=11630). The protein contains three functional domains important for dimerisation, DNA binding and transactivation [6].…”