Allosteric rescue of catalytically impaired ATP phosphoribosyltransferase variants links protein dynamics to active-site electrostatic preorganisation

Gemma Fisher, Marina Corbella, Magnus S. Alphey, John Nicholson, Benjamin J. Read, Shina C. L. Kamerlin () and Rafael G. da Silva ()
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Gemma Fisher: University of St Andrews
Marina Corbella: Uppsala University
Magnus S. Alphey: University of St Andrews
John Nicholson: University of St Andrews
Benjamin J. Read: University of St Andrews
Shina C. L. Kamerlin: Uppsala University
Rafael G. da Silva: University of St Andrews

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract ATP phosphoribosyltransferase catalyses the first step of histidine biosynthesis and is controlled via a complex allosteric mechanism where the regulatory protein HisZ enhances catalysis by the catalytic protein HisGS while mediating allosteric inhibition by histidine. Activation by HisZ was proposed to position HisGS Arg56 to stabilise departure of the pyrophosphate leaving group. Here we report active-site mutants of HisGS with impaired reaction chemistry which can be allosterically restored by HisZ despite the HisZ:HisGS interface lying ~20 Å away from the active site. MD simulations indicate HisZ binding constrains the dynamics of HisGS to favour a preorganised active site where both Arg56 and Arg32 are poised to stabilise leaving-group departure in WT-HisGS. In the Arg56Ala-HisGS mutant, HisZ modulates Arg32 dynamics so that it can partially compensate for the absence of Arg56. These results illustrate how remote protein-protein interactions translate into catalytic resilience by restoring damaged electrostatic preorganisation at the active site.

Date: 2022
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DOI: 10.1038/s41467-022-34960-9

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