The Mammalian High Mobility Group Protein AT-Hook 2 (HMGA2): Biochemical and Biophysical Properties, and Its Association with Adipogenesis.

Linjia Su,Fenfei Leng,Zifang Deng

doi:10.3390/ijms21103710

Abstract

The mammalian high-mobility-group protein AT-hook 2 (HMGA2) is a small DNA-binding protein and consists of three “AT-hook” DNA-binding motifs and a negatively charged C-terminal motif. It is a multifunctional nuclear protein directly linked to obesity, human height, stem cell youth, human intelligence, and tumorigenesis. Biochemical and biophysical studies showed that HMGA2 is an intrinsically disordered protein (IDP) and could form homodimers in aqueous buffer solution. The “AT-hook” DNA-binding motifs specifically bind to the minor groove of AT-rich DNA sequences and induce DNA-bending. HMGA2 plays an important role in adipogenesis most likely through stimulating the proliferative expansion of preadipocytes and also through regulating the expression of transcriptional factor Peroxisome proliferator-activated receptor γ (PPARγ) at the clonal expansion step from preadipocytes to adipocytes. Current evidence suggests that a main function of HMGA2 is to maintain stemness and renewal capacity of stem cells by which HMGA2 binds to chromosome and lock chromosome into a specific state, to allow the human embryonic stem cells to maintain their stem cell potency. Due to the importance of HMGA2 in adipogenesis and tumorigenesis, HMGA2 is considered a potential therapeutic target for anticancer and anti-obesity drugs. Efforts are taken to identify inhibitors targeting HMGA2.

Highlights

The mammalian high-mobility-group protein AT-hook 2 (HMGA2) is a non-histone chromosome protein and belongs to the HMGA family, which includes four members: HMGA1a, 1b, 1c, and HMGA2 [1]
It looks likely that the main functions of HMGA2 are promoting cell proliferation and maintaining the stemness potency of stem cells
This hypothesis is in contrast with the previous belief that HMGA2 serves as a transcriptional factor or an architecture/general transcriptional factor, to promote or inhibit transcription only

Summary

Introduction

The mammalian high-mobility-group protein AT-hook 2 (HMGA2) is a non-histone chromosome protein and belongs to the HMGA family, which includes four members: HMGA1a, 1b, 1c, and HMGA2 [1]. HMGA1a, 1b, and 1c are the different splicing products of the same gene, the HMGA1 gene [2]. High-mobility-group proteins were discovered, identified, and isolated by Graham H. The protein sequences of murine and human HMGA2 are almost identical, except for five amino acid residues. None of these five amino acid residues is located in the “AT-hook” DNA-binding motifs [3,13]. The 3 UTR carries multiple microRNA Let-7 binding sites that negatively regulate HMGA2 expression in development and tumorigenesis [17,18,19]

Biochemical and Biophysical Properties of HMGA2

HMGA2 in Adipogenesis

Findings

Conclusions and Perspectives