Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation

Nat Struct Mol Biol. 2010 Nov;17(11):1352-7. doi: 10.1038/nsmb.1918. Epub 2010 Oct 17.

Abstract

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 α-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphatases / physiology*
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Crystallography, X-Ray
  • Hydrogen Bonding
  • Models, Molecular
  • Mycobacterium / metabolism*
  • Protein Folding
  • Protein Interaction Mapping
  • Ubiquitins / chemistry
  • Ubiquitins / metabolism*

Substances

  • Bacterial Proteins
  • Pup protein, Mycobacterium tuberculosis
  • Ubiquitins
  • Adenosine Triphosphatases
  • Mpa protein, Mycobacterium tuberculosis

Associated data

  • PDB/3M91
  • PDB/3M9B
  • PDB/3M9D
  • PDB/3M9H