Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction.
The alarmone (p)ppGpp regulates diverse targets, yet its target specificity and evolution remain poorly understood. Here, we elucidate the mechanism by which basal (p)ppGpp inhibits the purine salvage enzyme HPRT by sharing a conserved motif with its substrate PRPP. Intriguingly, HPRT regulation by (p)ppGpp varies across organisms and correlates with HPRT oligomeric forms. (p)ppGpp-sensitive HPRT exists as a PRPP-bound dimer or an apo- and (p)ppGpp-bound tetramer, where a dimer-dimer interface triggers allosteric structural rearrangements to enhance (p)ppGpp inhibition. Loss of this oligomeric interface results in weakened (p)ppGpp regulation. Our results reveal an evolutionary principle whereby protein oligomerization allows evolutionary change to accumulate away from a conserved binding pocket to allosterically alter specificity of ligand interaction. This principle also explains how another (p)ppGpp target GMK is variably regulated across species. Since most ligands bind near protein interfaces, we propose that this principle extends to many other protein-ligand interactions.
['Anderson|Brent W|BW|0000-0003-2785-5343', 'Liu|Kuanqing|K|', 'Wolak|Christine|C|', 'Dubiel|Katarzyna|K|', 'She|Fukang|F|', 'Satyshur|Kenneth A|KA|0000-0001-9371-2493', 'Keck|James L|JL|', 'Wang|Jue D|JD|0000-0003-1503-170X']
D000494:Allosteric Regulation D001412:Bacillus subtilis D018360:Crystallography, X-Ray D004926:Escherichia coli D006158:Guanosine Pentaphosphate D006159:Guanosine Tetraphosphate D007041:Hypoxanthine Phosphoribosyltransferase D011487:Protein Conformation D055503:Protein Multimerization
(p)ppGpp B. subtilis allosteric regulation bacterial homeostasis biochemistry chemical biology enzyme oligomerization protein evolution signaling ligand