Binding-induced Folding of Prokaryotic Ubiquitin-like Protein on the Mycobacterium Proteasomal ATPase Targets Substrates for Degradation
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.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Organization:
- USDOE SC OFFICE OF SCIENCE (SC)
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 1041962
- Report Number(s):
- BNL-97640-2012-JA; TRN: US201212%%373
- Journal Information:
- Nature Structural and Molecular Biology, Vol. 17, Issue 11; ISSN 1545-9993
- Country of Publication:
- United States
- Language:
- English
Similar Records
"Depupylation" of Prokaryotic Ubiquitin-like Protein from Mycobacterial Proteasome Substrates
Structural Insights on the Mycobacterium tuberculosis Proteasomal ATPase Mpa