8EC6

Cryo-EM structure of the Glutaminase C core filament (fGAC)

Summary for 8EC6

• Entry DOI: 10.2210/pdb8ec6/pdb
• EMDB information: 28013
• Descriptor: Isoform 2 of Glutaminase kidney isoform, mitochondrial, PHOSPHATE ION (2 entities in total)
• Functional Keywords: mitochondria, filament, hydrolase
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 8
• Total formula weight: 427375.46

Authors

Ambrosio, A.L.,Dias, S.M.,Quesnay, J.E.,Portugal, R.V.,Cassago, A.,van Heel, M.G.,Islam, Z.,Rodrigues, C.T. (deposition date: 2022-09-01, release date: 2023-09-20, Last modification date: 2023-12-27)

Primary citation

Adamoski, D.,Dias, M.M.,Quesnay, J.E.N.,Yang, Z.,Zagoriy, I.,Steyer, A.M.,Rodrigues, C.T.,da Silva Bastos, A.C.,da Silva, B.N.,Costa, R.K.E.,de Abreu, F.M.O.,Islam, Z.,Cassago, A.,van Heel, M.G.,Consonni, S.R.,Mattei, S.,Mahamid, J.,Portugal, R.V.,Ambrosio, A.L.B.,Dias, S.M.G.
Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.
Nat.Struct.Mol.Biol., 30:1902-1912, 2023

PubMed Abstract: Glutaminase (GLS), which deaminates glutamine to form glutamate, is a mitochondrial tetrameric protein complex. Although inorganic phosphate (Pi) is known to promote GLS filamentation and activation, the molecular basis of this mechanism is unknown. Here we aimed to determine the molecular mechanism of Pi-induced mouse GLS filamentation and its impact on mitochondrial physiology. Single-particle cryogenic electron microscopy revealed an allosteric mechanism in which Pi binding at the tetramer interface and the activation loop is coupled to direct nucleophile activation at the active site. The active conformation is prone to enzyme filamentation. Notably, human GLS filaments form inside tubulated mitochondria following glutamine withdrawal, as shown by in situ cryo-electron tomography of cells thinned by cryo-focused ion beam milling. Mitochondria with GLS filaments exhibit increased protection from mitophagy. We reveal roles of filamentous GLS in mitochondrial morphology and recycling.

PubMed: 37857822
DOI: 10.1038/s41594-023-01118-0

Experimental method

ELECTRON MICROSCOPY (3.1 Å)