Activity of the mycobacterial proteasomal ATPase Mpa is reversibly regulated by pupylation |
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Authors: | Delley Cyrille L Striebel Frank Heydenreich Franziska M Özcelik Dennis Weber-Ban Eilika |
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Institution: | Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland. |
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Abstract: | Pupylation is a bacterial post-translational modification of target proteins on lysine residues with prokaryotic ubiquitin-like protein Pup. Pup-tagged substrates are recognized by a proteasome-interacting ATPase termed Mpa in Mycobacterium tuberculosis. Mpa unfolds pupylated substrates and threads them into the proteasome core particle for degradation. Interestingly, Mpa itself is also a pupylation target. Here, we show that the Pup ligase PafA predominantly produces monopupylated Mpa modified homogeneously on a single lysine residue within its C-terminal region. We demonstrate that this modification renders Mpa functionally inactive. Pupylated Mpa can no longer support Pup-mediated proteasomal degradation due to its inability to associate with the proteasome core. Mpa is further inactivated by rapid Pup- and ATPase-driven deoligomerization of the hexameric Mpa ring. We show that pupylation of Mpa is chemically and functionally reversible. Mpa regains its enzymatic activity upon depupylation by the depupylase Dop, affording a rapid and reversible activity control over Mpa function. |
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Keywords: | ATP-dependent Protease ATPases Mycobacterium tuberculosis Proteasome Protein Degradation Ubiquitination Mpa Post-translational Modification Prokaryotic Ubiquitin-like Protein Pupylation |
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