A deubiquitylase with an unusually high-affinity ubiquitin-binding domain from the scrub typhus pathogen Orientia tsutsugamushi

Jason M. Berk, Christopher Lim, Judith A. Ronau, Apala Chaudhuri, Hongli Chen, John F. Beckmann, J. Patrick Loria, Yong Xiong () and Mark Hochstrasser ()
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Jason M. Berk: Yale University
Christopher Lim: Yale University
Judith A. Ronau: Yale University
Apala Chaudhuri: Yale University
Hongli Chen: Yale University
John F. Beckmann: Yale University
J. Patrick Loria: Yale University
Yong Xiong: Yale University
Mark Hochstrasser: Yale University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15985-4

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