Dimerization defective MODY mutations of hepatocyte nuclear factor 4α

Puja Singh, Shu Ping Tung, Eun Hee Han, In Kyu Lee, Young-In Chi

Research output: Contribution to journalArticlepeer-review

Abstract

HNF4α is a culprit gene product for a monogenic and dominantly-inherited form of diabetes, referred to as MODY1 (Maturity Onset Diabetes of the Young type 1). Reduced HNF4α activities have been linked to impaired insulin secretion and β-cell function. Numerous mutations have been identified from the patients and they have been instructive as to the individual residue's role in protein structure-function and dysfunction. As a member of the nuclear receptor (NR) superfamily, HNF4α is made of characteristic modular domains and it functions exclusively as a homodimer despite its sequence homology to RXR, a common heterodimer partner of non-steroidal NRs. Transcription factors commonly dimerize to enhance their molecular functions mainly by facilitating the recognition of double helix target DNAs that display an intrinsic pseudo-2-fold symmetry and the recruitment of the remainder of the main transcriptional machinery. HNF4α is no exception and its dimerization is maintained by the ligand binding domain (LBD) mainly through the leucine-zipper-like interactions at the stalk of two interacting helices. Although many MODY1 mutations have been previously characterized, including DNA binding disruptors, ligand binding disruptors, coactivator binding disruptors, and protein stability disruptors, protein dimerization disruptors have not been formally reported. In this report, we present a set of data for the two MODY1 mutations found right at the dimerization interface (L332 P and L328del mutations) which clearly exhibit the disruptive effects of directly affecting dimerization, protein stability, and transcriptional activities. These data reinforced the fact that MODY mutations are loss-of-function mutations and HNF4α dimerization is essential for its optimal function and normal physiology.

Original languageEnglish (US)
Pages (from-to)1-6
Number of pages6
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume814
DOIs
StatePublished - Mar 2019

Bibliographical note

Funding Information:
We thank Dr. Jiun-Jr Wang at the Fu-Jen Catholic University for his assistance in the initial identification of HNF4α mutations from the MODY patients. This work was supported by the American Diabetes Association ( 7-08-CD-03 ) and the Brain Pool Program funded by the Ministry of Science and ICT through the National Research Foundation of Korea (2018H1D3A2000849) to YC, and the Korea Health technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea ( HI16C1501 ) and the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean Government (NRF- 2016M3A9B6902872 ) to IL.

Publisher Copyright:
© 2019 Elsevier B.V.

Keywords

  • Diabetes
  • Dimerization
  • Gene regulation
  • HNF4α
  • MODY
  • Mutation
  • Nuclear receptor
  • Protein stability

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