Dimerization defective MODY mutations of hepatocyte nuclear factor 4α. Mutat Res 2019 Mar;814:1-6
Date
01/17/2019Pubmed ID
30648609DOI
10.1016/j.mrfmmm.2019.01.002Scopus ID
2-s2.0-85059814306 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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.
Author List
Singh P, Tung SP, Han EH, Lee IK, Chi YIAuthor
Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Diabetes Mellitus, Type 2Dimerization
HeLa Cells
Hepatocyte Nuclear Factor 4
Humans
Loss of Function Mutation
Models, Molecular
Mutagenesis, Site-Directed
Mutation
Protein Binding
Protein Interaction Domains and Motifs
Protein Multimerization
Protein Stability
Protein Structure, Quaternary
Transcriptional Activation
