Abstract
The mammalian high mobility group protein AT-hook 2 (HMGA2) is a chromosomal architectural transcription factor involved in cell transformation and oncogenesis. It consists of three positively charged “AT-hooks” and a negatively charged C-terminus. Sequence analyses, circular dichroism experiments, and gel-filtration studies showed that HMGA2, in the native state, does not have a defined secondary or tertiary structure. Surprisingly, using combined approaches of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) chemical cross-linking, analytical ultracentrifugation, fluorescence resonance energy transfer (FRET), and mass spectrometry, we discovered that HMGA2 is capable of self-associating into homodimers in aqueous buffer solution. Our results showed that electrostatic interactions between the positively charged “AT-hooks” and the negatively charged C-terminus greatly contribute to the homodimer formation.
Highlights
The mammalian high mobility group protein AT-hook 2 (HMGA2) is a nonhistone chromosomal protein expressed almost exclusively in undifferentiated mesenchymal cells [1]
The high contents of the basic amino acid residues make HMGA2 a high isoelectric point protein
Our Circular dichroism (CD) studies showed that HMGA2 is an unstructured protein
Summary
The mammalian high mobility group protein AT-hook 2 (HMGA2) is a nonhistone chromosomal protein expressed almost exclusively in undifferentiated mesenchymal cells [1]. Work from Chada’s laboratory showed that Hmga knock-out mice developed pygmy phenotype [1] These mutant mice were severely deficient in fat cells and other mesenchymal tissues. The same group demonstrated that disruption of Hmga gene caused a dramatic reduction in obesity of leptin-deficient mice (Lepob/Lepob) in a gene dosage dependent manner: Hmga2+/+ Lepob/Lepob mice weighed over three times more than Hmga2-/Lepob/Lepob animals, and the weight of Hmga2+/- Lepob/Lepob mice was in between [3] These results suggest that HMGA2 plays an important role in fat cell proliferation and may be a target for the treatment of obesity [3,4].
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