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Electrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA

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  • Matthias F. Block

    (Institute of Molecular Biology & Biophysics)

  • Cyrille L. Delley

    (Institute of Molecular Biology & Biophysics
    University of California)

  • Lena M. L. Keller

    (Institute of Molecular Biology & Biophysics)

  • Timo T. Stuehlinger

    (Institute of Molecular Biology & Biophysics)

  • Eilika Weber-Ban

    (Institute of Molecular Biology & Biophysics)

Abstract

Pupylation, a post-translational modification found in Mycobacterium tuberculosis and other Actinobacteria, involves the covalent attachment of prokaryotic ubiquitin-like protein (Pup) to lysines on target proteins by the ligase PafA (proteasome accessory factor A). Pupylated proteins, like ubiquitinated proteins in eukaryotes, are recruited for proteasomal degradation. Proteomic studies suggest that hundreds of potential pupylation targets are modified by the sole existing ligase PafA. This raises intriguing questions regarding the selectivity of this enzyme towards a diverse range of substrates. Here, we show that the availability of surface lysines alone is not sufficient for interaction between PafA and target proteins. By identifying the interacting residues at the pupylation site, we demonstrate that PafA recognizes authentic substrates via a structural recognition motif centered around exposed lysines. Through a combination of computational analysis, examination of available structures and pupylated proteomes, and biochemical experiments, we elucidate the mechanism by which PafA achieves recognition of a wide array of substrates while retaining selective protein turnover.

Suggested Citation

  • Matthias F. Block & Cyrille L. Delley & Lena M. L. Keller & Timo T. Stuehlinger & Eilika Weber-Ban, 2023. "Electrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40807-8
    DOI: 10.1038/s41467-023-40807-8
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    References listed on IDEAS

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