HMGI/Y proteins: flexible regulators of transcription and chromatin structure

The mammalian HMGI/Y (HMGA) non-histone proteins participate in a wide variety of cellular processes including regulation of inducible gene transcription, integration of retroviruses into chromosomes and the induction of neoplastic transformation and promotion of metastatic progression of cancer cells. Recent advances have contributed greatly to our understanding of how the HMGI/Y proteins participate in the molecular mechanisms underlying these biological events. All members of the HMGI/Y family of 'high mobility group' proteins are characterized by the presence of multiple copies of a conserved DNA-binding peptide motif called the 'AT hook' that preferentially binds to the narrow minor groove of stretches of AT-rich sequence. The mammalian HMGI/Y proteins have little, if any, secondary structure in solution but assume distinct conformations when bound to substrates such as DNA or other proteins. Their intrinsic flexibility allows the HMGI/Y proteins to participate in specific protein-DNA and protein-protein interactions that induce both structural changes in chromatin substrates and the formation of stereospecific complexes called 'enhanceosomes' on the promoter/enhancer regions of genes whose transcription they regulate. The formation of such regulatory complexes is characterized by reciprocal inductions of conformational changes in both the HMGI/Y proteins themselves and in their interacting substrates. It may well be that the inherent flexibility of the HMGI/Y proteins, combined with their ability to undergo reversible disordered-to-ordered structural transitions, has been a significant factor in the evolutionary selection of these proteins for their functional role(s) in cells.