Abstract |
Ubiquitin mediated signaling contributes critically to host cell defenses during pathogen infection. Many pathogens manipulate the ubiquitin system to evade these defenses. Here we characterize a likely effector protein bearing a deubiquitylase (DUB) domain from the obligate intracellular bacterium Orientia tsutsugamushi, the causative agent of scrub typhus. The Ulp1-like DUB prefers ubiquitin substrates over ubiquitin-like proteins and efficiently cleaves polyubiquitin chains of three or more ubiquitins. The co-crystal structure of the DUB (OtDUB) domain with ubiquitin revealed three bound ubiquitins: one engages the S1 site, the second binds an S2 site contributing to chain specificity and the third binds a unique ubiquitin-binding domain (UBD). The UBD modulates OtDUB activity, undergoes a pronounced structural transition upon binding ubiquitin, and binds monoubiquitin with an unprecedented ~5 nM dissociation constant. The characterization and high-resolution structure determination of this enzyme should aid in its development as a drug target to counter Orientia infections.
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Authors | Jason M Berk, Christopher Lim, Judith A Ronau, Apala Chaudhuri, Hongli Chen, John F Beckmann, J Patrick Loria, Yong Xiong, Mark Hochstrasser |
Journal | Nature communications
(Nat Commun)
Vol. 11
Issue 1
Pg. 2343
(05 11 2020)
ISSN: 2041-1723 [Electronic] England |
PMID | 32393759
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- Bacterial Proteins
- Ubiquitins
- Lysine
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Topics |
- Amino Acid Sequence
- Bacterial Proteins
(chemistry, metabolism)
- Binding Sites
- Crystallography, X-Ray
- Hydrophobic and Hydrophilic Interactions
- Lysine
(metabolism)
- Orientia tsutsugamushi
(enzymology)
- Protein Binding
- Protein Domains
- Scrub Typhus
(microbiology)
- Substrate Specificity
- Thermodynamics
- Ubiquitins
(metabolism)
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