1. Architecture and function of human uromodulin filaments in urinary tract infections
- Author
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Markus Aebi, Dawid Zyla, Rudi Glockshuber, Johannes Trück, Jessica J Stanisich, Olivier Devuyst, Chia-Wei Lin, Maximilian M. Sauer, Jonathan Eras, Martin Pilhofer, Gregor L. Weiss, University of Zurich, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, and UCL - (SLuc) Service de néphrologie
- Subjects
0301 basic medicine ,Glycosylation ,Tamm–Horsfall protein ,610 Medicine & health ,macromolecular substances ,030204 cardiovascular system & hematology ,Biology ,Ligands ,Pilus ,Epitope ,10052 Institute of Physiology ,Protein filament ,03 medical and health sciences ,0302 clinical medicine ,Uromodulin ,Humans ,Adhesins, Bacterial ,1000 Multidisciplinary ,Multidisciplinary ,Cryoelectron Microscopy ,Adhesion ,In vitro ,3. Good health ,Cell biology ,Bacterial adhesin ,030104 developmental biology ,Urinary Tract Infections ,biology.protein ,570 Life sciences ,biology ,Function (biology) - Abstract
Uromodulin is the most abundant protein in human urine, and it forms filaments that antagonize the adhesion of uropathogens; however, the filament structure and mechanism of protection remain poorly understood. We used cryo–electron tomography to show that the uromodulin filament consists of a zigzag-shaped backbone with laterally protruding arms. N-glycosylation mapping and biophysical assays revealed that uromodulin acts as a multivalent ligand for the bacterial type 1 pilus adhesin, presenting specific epitopes on the regularly spaced arms. Imaging of uromodulin-uropathogen interactions in vitro and in patient urine showed that uromodulin filaments associate with uropathogens and mediate bacterial aggregation, which likely prevents adhesion and allows clearance by micturition. These results provide a framework for understanding uromodulin in urinary tract infections and in its more enigmatic roles in physiology and disease. ISSN:0036-8075 ISSN:1095-9203
- Published
- 2020
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