Structural highlights
Function
[PUP_MYCTU] Protein modifier that is covalently attached to lysine residues of substrate proteins, thereby targeting them for proteasomal degradation. The tagging system is termed pupylation. Among the identified substrates are the FabD, PanB and Mpa proteins.[1] [2] [3]
Publication Abstract from PubMed
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.
Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation.,Wang T, Darwin KH, Li H Nat Struct Mol Biol. 2010 Oct 17. PMID:20953180[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pearce MJ, Mintseris J, Ferreyra J, Gygi SP, Darwin KH. Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis. Science. 2008 Nov 14;322(5904):1104-7. doi: 10.1126/science.1163885. Epub 2008, Oct 2. PMID:18832610 doi:http://dx.doi.org/10.1126/science.1163885
- ↑ Striebel F, Imkamp F, Sutter M, Steiner M, Mamedov A, Weber-Ban E. Bacterial ubiquitin-like modifier Pup is deamidated and conjugated to substrates by distinct but homologous enzymes. Nat Struct Mol Biol. 2009 Jun;16(6):647-51. doi: 10.1038/nsmb.1597. Epub 2009 May, 17. PMID:19448618 doi:http://dx.doi.org/10.1038/nsmb.1597
- ↑ Burns KE, Pearce MJ, Darwin KH. Prokaryotic ubiquitin-like protein provides a two-part degron to Mycobacterium proteasome substrates. J Bacteriol. 2010 Jun;192(11):2933-5. doi: 10.1128/JB.01639-09. Epub 2010 Mar 16. PMID:20233925 doi:http://dx.doi.org/10.1128/JB.01639-09
- ↑ Wang T, Darwin KH, Li H. Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation. Nat Struct Mol Biol. 2010 Oct 17. PMID:20953180 doi:10.1038/nsmb.1918
