Heterotropic regulation and negative homotropic cooperativity.

Heterotropic regulation of protein function is crucial for such diverse cellular events as transcription, signal transduction, enzymatic activity, transport and many others. It is achieved via ligand-induced changes in protein structure and is often coupled to homotropic cooperativity. In this work, we compare the structural and functional properties of a set of evolutionarily unrelated proteins that present heterotropic regulation and negative homotropic cooperativity, for at least some of their ligands. This set is limited because the coupling of negative cooperativity and heterotropic regulation occurs rarely. Nevertheless, we identified some recurring structural features among the proteins in our dataset. All of these proteins: (i) are homo-oligomers; (ii) have a one ligand per subunit binding stoichiometry both for their primary ligands/substrates and their effectors; (iii) do not require complete saturation with their effectors to reach maximum activation or inhibition; and (iv) show peculiar intersubunit ligand-induced asymmetry. Together, these results imply that heterotropic regulation acts at the quaternary, as well as tertiary, structure level.