Protein conformational changes and dynamics play critical roles in delivering enzyme function. This talk will examine how changes in quaternary structure can regulate catalysis in ATP phosphoribosyltransferase, the enzyme that catalyses the first committed step of histidine biosynthesis.
Histidine biosynthesis is a metabolically expensive pathway and is tightly regulated by feedback inhibition from histidine. In some bacteria and archaea, this regulation is mediated through a two-protein system in which the catalytic HisG subunit associates with a regulatory HisZ subunit to form an active hetero-octameric complex. HisG alone is a weak catalyst, but interaction with HisZ produces an enzyme assembly capable of responding to substrate and inhibitor binding.
We have used the Staphylococcus aureus HisZG complex as a model to explore how ligand binding, protein assembly and catalytic activity are coupled. Structural and biochemical studies reveal how the HisZG complex can shift between active and less active states through changes in oligomeric assembly, providing an unusual mechanism for allosteric regulation. Comparison with related HisZG systems suggests that different members of this enzyme family can regulate a conserved HisG catalytic core through distinct structural mechanisms.
These findings provide new insight into the evolution of allostery in metabolic enzymes and highlight protein–protein interfaces as important regulatory elements in amino acid biosynthesis.