Allosteric role of the citrate synthase homology domain of ATP citrate lyase

Xuepeng Wei, Kollin Schultz, Hannah L. Pepper, Emily Megill, Austin Vogt, Nathaniel W. Snyder and Ronen Marmorstein ()
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Xuepeng Wei: University of Pennsylvania
Kollin Schultz: University of Pennsylvania
Hannah L. Pepper: Temple University
Emily Megill: Temple University
Austin Vogt: University of Pennsylvania
Nathaniel W. Snyder: Temple University
Ronen Marmorstein: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract ATP citrate lyase (ACLY) is the predominant nucleocytosolic source of acetyl-CoA and is aberrantly regulated in many diseases making it an attractive therapeutic target. Structural studies of ACLY reveal a central homotetrameric core citrate synthase homology (CSH) module flanked by acyl-CoA synthetase homology (ASH) domains, with ATP and citrate binding the ASH domain and CoA binding the ASH-CSH interface to produce acetyl-CoA and oxaloacetate products. The specific catalytic role of the CSH module and an essential D1026A residue contained within it has been a matter of debate. Here, we report biochemical and structural analysis of an ACLY-D1026A mutant demonstrating that this mutant traps a (3S)-citryl-CoA intermediate in the ASH domain in a configuration that is incompatible with the formation of acetyl-CoA, is able to convert acetyl-CoA and OAA to (3S)-citryl-CoA in the ASH domain, and can load CoA and unload acetyl-CoA in the CSH module. Together, this data support an allosteric role for the CSH module in ACLY catalysis.

Date: 2023
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DOI: 10.1038/s41467-023-37986-9

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