ENTROPY REDISTRIBUTION DRIVES ALLOSTERY IN A METALLOREGULATORY PROTEIN

DAIANA ANDREA CAPDEVILA; JOSEPH BRAYMER; KATHERINE EDMONDS; HONGWEI WU; DAVID GIEDROC

Queretaro

Congreso; V Latin American Meeting on Biological Inorganic Chemistry; 2016

Society of Biological Inorganic Chemistry

In bacteria, metalloregulatory proteins are central to transition metal ion balance. These proteins employ allostery to connect metal binding to DNA binding, which regulates transcription of genes that control metal homeostasis. We propose a model of allostery in a compact, single domain metalloregulatory protein that can be entirely explained by a redistribution of site-specific conformational entropy. We use a well-developed model system, a zinc (Zn)-sensing transcriptional repressor from the Staphylococcus aureus, to provide unprecedented insights into heterotropic allostery, the inhibition of DNA operator binding by the allosteric ligand Zn. By employing methyl groups as reporters of conformational entropy, we show that Zn binding renders inaccessible a highly dynamic DNA-bound conformation. We further show for the first time, that these entropic fingerprints pinpoint ?hot spots? that when mutated, specifically impair allosteric coupling of Zn and DNA binding. Finally, we show that these hot spots define a limited number of sites that nature has exploited to evolve and expand the extraordinary functional diversity of this family of bacterial repressors. We postulate that our findings are representative of many compact proteins where a redistribution of dynamical disorder is used to drive biological regulation.This hypothesis will be tested extending the model to other transcriptional regulators. Particularly, we will discuss Zn-mediated allosteric activation in a repressor derived from a related structural family.