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PreprintCited by 10Protein Structure and DynamicsGenomics and Chromatin DynamicsPancreatic function and diabetes

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Structural properties of the HNF-1A transactivation domain

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Kind, Laura, Driver, Mark, Raasakka, Arne, Onck, Patrick R., Njølstad, Pål Rasmus, Arnesen, Thomas, Kursula, Petri·2023·Frontiers in Molecular Biosciences
DOI 10.1101/2023.06.23.546236PMC PMC10613711

Preprint — published as 10.3389/fmolb.2023.1249939 · Paper page

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Abstract

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.

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Metadata

Authors
Kind, L., Driver, M., Raasakka, A., Onck, P. R., Njølstad, P. R., Arnesen, T., & Kursula, P.
Affiliations
  • University of Bergen (NO)
  • University of Groningen (NL)
  • Haukeland University Hospital (NO)
Corresponding author
Kind, Laura
ORCID
Venue
Frontiers in Molecular Biosciences
Publisher
openRxiv
Published
2023-06-23
Volume
10
Pages
1249939-1249939
ISSN
2296-889X (ISSN-L)
DOI
10.1101/2023.06.23.546236
PMC
PMC10613711
OpenAlex
W4387670227
Cited by
10
References
1
Citations by year
2026: 4 · 2025: 3 · 2024: 3
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Molecular Biosciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • European Commission (847675, HORIZON2020)
  • Rijksuniversiteit Groningen
  • Universitetet i Bergen
  • Norges Forskningsråd (245922, 245828)
  • Oulun Yliopisto
  • Novo Nordisk Fonden (NNF18OC0054741)
  • Biocenter, University of Oulu
  • Center for Information Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Keywords
transactivation domain, transcription factors, pancreatic beta cells, HNF1A-MODY, type 2 diabetes, protein disorder, liquid-liquid phase separation, protein-protein interaction motifs, gene transcription, recombinant protein expression and purification, small-angle X-ray scattering, synchrotron radiation circular dichroism

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