Schloetzer, Jan and Schmalix, Alexander and Huegelschaeffer, Sophie and Rieger, Dominic and Sauer, Florian and Tully, Mark D. and Rudel, Thomas and Wiesner, Silke and Kisker, Caroline (2024) Linkage-specific ubiquitin binding interfaces modulate the activity of the chlamydial deubiquitinase Cdu1 towards poly-ubiquitin substrates. PLOS PATHOGENS, 20 (10): e1012630. ISSN 1553-7366, 1553-7374
Full text not available from this repository. (Request a copy)Abstract
The chlamydial deubiquitinase Cdu1 of the obligate intracellular human pathogenic bacterium Chlamydia trachomatis plays important roles in the maintenance of chlamydial infection. Despite the structural similarities shared with its homologue Cdu2, both DUBs display remarkable differences in their enzymatic activity towards poly-UB chain substrates. Whereas Cdu1 is highly active towards K48- and K63- poly-UB chains, Cdu2 activity is restricted mostly to mono-UB substrates. Here, we shed light on the molecular mechanisms of the differential activity and the substrate specificity of Cdu1 to better understand the cellular processes it is involved in, including infection-related events. We found that the strikingly elevated activity of Cdu1 relative to its paralogue Cdu2 can be attributed to an N-terminally extended alpha-helix, which has not been observed in Cdu2. Moreover, by employing isothermal titration calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate the differential recognition of K48- and K63-linked poly-UB substrates by Cdu1. Whereas K63-linked poly-UB substrates appear to be recognized by Cdu1 with only two independent ubiquitin interaction sites, up to four different binding interfaces are present for K48-linked ubiquitin chains. Combined, our data suggest that Cdu1 possesses a poly-UB chain directed activity that may enable its function as a multipurpose DUB with a broad substrate specificity. As a post-translational modification ubiquitination plays key roles in virtually all cellular processes and is also involved in the host immune response upon infection with intracellular pathogens. Chlamydia trachomatis secretes the two deubiquitinase effector proteins Cdu1 and Cdu2, which can subvert the host cell ubiquitin signaling and play crucial roles during infection. Both deubiquitinases have been shown to display drastic differences in their activity towards poly-ubiquitin chains. We here identified the molecular mechanisms by which the enhanced activity of Cdu1 towards these substrates is mediated. Moreover, we discovered marked differences in the recognition of differently linked poly-ubiquitin chains by Cdu1 and mapped binding sites for the individual ubiquitin moieties. Our study thus provides new insights into the enzymatic mechanisms of chlamydial deubiquitinases, which can be crucial to understand their distinct roles during infection.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | POLYUBIQUITIN; MECHANISMS; REVEALS; BIOSAXS; SYSTEM; DOMAIN |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Prof. Dr. Remco Sprangers |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jan 2026 06:42 |
| Last Modified: | 28 Jan 2026 06:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/64793 |
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