8Z02

CoA bound to human GTP-specific succinyl-CoA synthetase

Summary for 8Z02

• Entry DOI: 10.2210/pdb8z02/pdb
• Descriptor: Succinate--CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial, Succinate--CoA ligase [GDP-forming] subunit beta, mitochondrial, COENZYME A, ... (5 entities in total)
• Functional Keywords: gtp-specific succinyl-coa synthetase, gtpscs, lactyl-coa ligase, ligase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 77740.42

Authors

Liu, R.L.,Ren, X.L.,Li, L.T.,Zhang, Y.,Huang, H.,Zhao, Y.M. (deposition date: 2024-04-08, release date: 2024-12-11, Last modification date: 2025-02-19)

Primary citation

Liu, R.,Ren, X.,Park, Y.E.,Feng, H.,Sheng, X.,Song, X.,AminiTabrizi, R.,Shah, H.,Li, L.,Zhang, Y.,Abdullah, K.G.,Dubois-Coyne, S.,Lin, H.,Cole, P.A.,DeBerardinis, R.J.,McBrayer, S.K.,Huang, H.,Zhao, Y.
Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis.
Cell Metab., 37:377-, 2025

PubMed Abstract: Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.

PubMed: 39642882
DOI: 10.1016/j.cmet.2024.11.005

Experimental method

X-RAY DIFFRACTION (2.32 Å)