HMGA proteins

HMGA proteins flexible players in a structured world... 

Over the last several years a substantial body of evidence has accumulated indicating the types and patterns of secondary biochemical modifications present on histones [42,43], transcriptional co-activators [44] and the HMGA proteins [33]... 

Recent advances in mass spectrometry (MS) technology have provided researchers with an unparalleled ability to identify the types and patterns of secondary biochemical modifications found on proteins in living cells. Matrix-assisted laser desorption/ionization-MS (MALDI-MS) analyses have shown, for example, that HMGA proteins in vivo are simultaneously subject to complex patterns of phosphorylation, acetylation and methylation and that, within the same cell type, different isoforms of these proteins can exhibit quite different modification patterns [33]. Furthermore, these in vivo modifications have been demonstrated to markedly alter the binding affinity of HMGA proteins for both DNA and chromatin substrates in vitro [33]. Nevertheless, due to their number and complexity, it has been difficult to determine the actual biological function(s) played by these biochemical modifications in living cells. 

Fig. 6. Purified recombinant HMGA proteins bind to four regions of DNA on random sequence nucleosome core particles. Panel A The results of EMSA gel assays in which increasing concentrations of either purified nonhistone HMGN2 (a.k.a., HMG-17, which binds to two sites on nucleosome core particles) or recombinant human HMGAla protein were bound nucleosome core particles isolated from chicken erythrocytes [57]. Panel B Two different views of the nucleosome taken from the X-ray structure of Luger et al. [119] showing the sites of binding of HMGA proteins (dashed circles) determined by DNA foot-printing analyses and other techniques (see text for details).

Methods to lower the cellular concentrations of HMGA proteins... 

Refs. [82,83]) that can potentially be used to develop drugs that modulate the levels or functions of HMGA proteins in cells. 

Drugs that block binding of HMGA proteins to specific gene promoters... 

Drugs that specifically inactivate or cross-link HMGA proteins in vivo... 

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