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Article Dans Une Revue Nature Communications Année : 2022

Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR

Résumé

Large oligomeric enzymes control a myriad of cellular processes, from protein synthesis and degradation to metabolism. The 0.5 MDa large TET2 aminopeptidase, a prototypical protease important for cellular homeostasis, degrades peptides within a ca. 60 Å wide tetrahedral chamber with four lateral openings. The mechanisms of substrate trafficking and processing remain debated. Here, we integrate magic-angle spinning (MAS) NMR, mutagenesis, co-evolution analysis and molecular dynamics simulations and reveal that a loop in the catalytic chamber is a key element for enzymatic function. The loop is able to stabilize ligands in the active site and may additionally have a direct role in activating the catalytic water molecule whereby a conserved histidine plays a key role. Our data provide a strong case for the functional importance of highly dynamic - and often overlooked - parts of an enzyme, and the potential of MAS NMR to investigate their dynamics at atomic resolution.
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hal-03866731 , version 1 (10-11-2023)

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Diego Gauto, Pavel Macek, Duccio Malinverni, Hugo Fraga, Matteo Paloni, et al.. Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR. Nature Communications, 2022, 13, pp.1927. ⟨10.1038/s41467-022-29423-0⟩. ⟨hal-03866731⟩
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