Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 17, Issue 11, Pages 1352-U208Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1918
Keywords
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Funding
- Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy
- National Center for Research Resources of the US National Institutes of Health (NIH)
- NIH [AI070285, HL092774]
- Brookhaven National Laboratory LDRD
- Burroughs Wellcome Investigator in the Pathogenesis of Infectious Diseases award
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Mycobacterium tuberculosis uses a proteasome system that is analogous to the eukaryotic ubiquitin-proteasome pathway and is required for pathogenesis. However, the bacterial analog of ubiquitin, prokaryotic ubiquitin-like protein (Pup), is an intrinsically disordered protein that bears little sequence or structural resemblance to the highly structured ubiquitin. Thus, it was unknown how pupylated proteins were recruited to the proteasome. Here, we show that the Mycobacterium proteasomal ATPase (Mpa) has three pairs of tentacle-like coiled coils that recognize Pup. Mpa bound unstructured Pup through hydrophobic interactions and a network of hydrogen bonds, leading to the formation of an alpha-helix in Pup. Our work describes a binding-induced folding recognition mechanism in the Pup-proteasome system that differs mechanistically from substrate recognition in the ubiquitin-proteasome system. This key difference between the prokaryotic and eukaryotic systems could be exploited for the development of a small molecule-based treatment for tuberculosis.
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