Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR.
Nat Commun
; 13(1): 1927, 2022 04 08.
Article
em En
| MEDLINE
| ID: mdl-35395851
ABSTRACT
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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1
Base de dados:
MEDLINE
Assunto principal:
Simulação de Dinâmica Molecular
/
Aminopeptidases
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article