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

Author

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  • Diego F. Gauto

    (Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS)
    Univ. Paris-Saclay)

  • Pavel Macek

    (Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS)
    Celonic AG)

  • Duccio Malinverni

    (St Jude Children’s Research Hospital)

  • Hugo Fraga

    (Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS)
    Faculdade de Medicina da Universidade do Porto
    i3S, Instituto de Investigacao e Inovacao em Saude, Universidade do Porto)

  • Matteo Paloni

    (Univ Montpellier, CNRS, INSERM)

  • Iva Sučec

    (Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS))

  • Audrey Hessel

    (Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS))

  • Juan Pablo Bustamante

    (IBB (CONICET-UNER))

  • Alessandro Barducci

    (Univ Montpellier, CNRS, INSERM)

  • Paul Schanda

    (Univ. Grenoble Alpes, CEA, CNRS, Institut de Biologie Structurale (IBS)
    Institute of Science and Technology Austria)

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.

Suggested Citation

  • Diego F. Gauto & Pavel Macek & Duccio Malinverni & Hugo Fraga & Matteo Paloni & Iva Sučec & Audrey Hessel & Juan Pablo Bustamante & Alessandro Barducci & Paul Schanda, 2022. "Functional control of a 0.5 MDa TET aminopeptidase by a flexible loop revealed by MAS NMR," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29423-0
    DOI: 10.1038/s41467-022-29423-0
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    References listed on IDEAS

    as
    1. Diego F. Gauto & Leandro F. Estrozi & Charles D. Schwieters & Gregory Effantin & Pavel Macek & Remy Sounier & Astrid C. Sivertsen & Elena Schmidt & Rime Kerfah & Guillaume Mas & Jacques-Philippe Colle, 2019. "Integrated NMR and cryo-EM atomic-resolution structure determination of a half-megadalton enzyme complex," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Vilius Kurauskas & Sergei A. Izmailov & Olga N. Rogacheva & Audrey Hessel & Isabel Ayala & Joyce Woodhouse & Anastasya Shilova & Yi Xue & Tairan Yuwen & Nicolas Coquelle & Jacques-Philippe Colletier &, 2017. "Slow conformational exchange and overall rocking motion in ubiquitin protein crystals," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
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