Structural properties of the HNF-1A transactivation domain
Hepatocyte nuclear factor 1α (HNF-1A) is a transcription factor with important gene regulatory roles in pancreatic β-cells. HNF1A gene variants are associated with a monogenic form of diabetes (HNF1A-MODY) or an increased risk for type 2 diabetes. While several pancreatic target genes of HNF-1A have...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1249939/full |
| _version_ | 1797659513588809728 |
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| author | Laura Kind Mark Driver Arne Raasakka Patrick R. Onck Pål Rasmus Njølstad Pål Rasmus Njølstad Thomas Arnesen Thomas Arnesen Petri Kursula Petri Kursula |
| author_facet | Laura Kind Mark Driver Arne Raasakka Patrick R. Onck Pål Rasmus Njølstad Pål Rasmus Njølstad Thomas Arnesen Thomas Arnesen Petri Kursula Petri Kursula |
| author_sort | Laura Kind |
| collection | DOAJ |
| description | Hepatocyte nuclear factor 1α (HNF-1A) is a transcription factor with important gene regulatory roles in pancreatic β-cells. HNF1A gene variants are associated with a monogenic form of diabetes (HNF1A-MODY) or an increased risk for type 2 diabetes. While several pancreatic target genes of HNF-1A have been described, a lack of knowledge regarding the structure-function relationships in HNF-1A prohibits a detailed understanding of HNF-1A-mediated gene transcription, which is important for precision medicine and improved patient care. Therefore, we aimed to characterize the understudied transactivation domain (TAD) of HNF-1A in vitro. We present a bioinformatic approach to dissect the TAD sequence, analyzing protein structure, sequence composition, sequence conservation, and the existence of protein interaction motifs. Moreover, we developed the first protocol for the recombinant expression and purification of the HNF-1A TAD. Small-angle X-ray scattering and synchrotron radiation circular dichroism suggested a disordered conformation for the TAD. Furthermore, we present functional data on HNF-1A undergoing liquid-liquid phase separation, which is in line with in silico predictions and may be of biological relevance for gene transcriptional processes in pancreatic β-cells. |
| first_indexed | 2024-03-11T18:16:12Z |
| format | Article |
| id | doaj.art-6d60e27d16fb4b7b8a3edf13ada0e079 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-03-11T18:16:12Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-6d60e27d16fb4b7b8a3edf13ada0e0792023-10-16T06:56:04ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-10-011010.3389/fmolb.2023.12499391249939Structural properties of the HNF-1A transactivation domainLaura Kind0Mark Driver1Arne Raasakka2Patrick R. Onck3Pål Rasmus Njølstad4Pål Rasmus Njølstad5Thomas Arnesen6Thomas Arnesen7Petri Kursula8Petri Kursula9Department of Biomedicine, University of Bergen, Bergen, NorwayZernike Institute for Advanced Materials, University of Groningen, Groningen, NetherlandsDepartment of Biomedicine, University of Bergen, Bergen, NorwayZernike Institute for Advanced Materials, University of Groningen, Groningen, NetherlandsMohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, NorwaySection of Endocrinology and Metabolism, Children and Youth Clinic, Haukeland University Hospital, Bergen, NorwayDepartment of Biomedicine, University of Bergen, Bergen, NorwayDepartment of Surgery, Haukeland University Hospital, Bergen, NorwayDepartment of Biomedicine, University of Bergen, Bergen, NorwayFaculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, FinlandHepatocyte nuclear factor 1α (HNF-1A) is a transcription factor with important gene regulatory roles in pancreatic β-cells. HNF1A gene variants are associated with a monogenic form of diabetes (HNF1A-MODY) or an increased risk for type 2 diabetes. While several pancreatic target genes of HNF-1A have been described, a lack of knowledge regarding the structure-function relationships in HNF-1A prohibits a detailed understanding of HNF-1A-mediated gene transcription, which is important for precision medicine and improved patient care. Therefore, we aimed to characterize the understudied transactivation domain (TAD) of HNF-1A in vitro. We present a bioinformatic approach to dissect the TAD sequence, analyzing protein structure, sequence composition, sequence conservation, and the existence of protein interaction motifs. Moreover, we developed the first protocol for the recombinant expression and purification of the HNF-1A TAD. Small-angle X-ray scattering and synchrotron radiation circular dichroism suggested a disordered conformation for the TAD. Furthermore, we present functional data on HNF-1A undergoing liquid-liquid phase separation, which is in line with in silico predictions and may be of biological relevance for gene transcriptional processes in pancreatic β-cells.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1249939/fullβ-celldiabetestranscription factorHNF-1AMODYintrinsically disordered protein |
| spellingShingle | Laura Kind Mark Driver Arne Raasakka Patrick R. Onck Pål Rasmus Njølstad Pål Rasmus Njølstad Thomas Arnesen Thomas Arnesen Petri Kursula Petri Kursula Structural properties of the HNF-1A transactivation domain Frontiers in Molecular Biosciences β-cell diabetes transcription factor HNF-1A MODY intrinsically disordered protein |
| title | Structural properties of the HNF-1A transactivation domain |
| title_full | Structural properties of the HNF-1A transactivation domain |
| title_fullStr | Structural properties of the HNF-1A transactivation domain |
| title_full_unstemmed | Structural properties of the HNF-1A transactivation domain |
| title_short | Structural properties of the HNF-1A transactivation domain |
| title_sort | structural properties of the hnf 1a transactivation domain |
| topic | β-cell diabetes transcription factor HNF-1A MODY intrinsically disordered protein |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1249939/full |
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