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The cryo-EM structure of the human uromodulin filament core reveals a unique assembly mechanism

Lookup NU author(s): Dr Eric OlingerORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2020, eLife Sciences Publications Ltd. All rights reserved.The glycoprotein uromodulin (UMOD) is the most abundant protein in human urine and forms filamentous homopolymers that encapsulate and aggregate uropathogens, promoting pathogen clearance by urine excretion. Despite its critical role in the innate immune response against urinary tract infections, the structural basis and mechanism of UMOD polymerization remained unknown. Here, we present the cryo-EM structure of the UMOD filament core at 3.5 Å resolution, comprised of the bipartite zona pellucida (ZP) module in a helical arrangement with a rise of ~65 Å and a twist of ~180°. The immunoglobulin-like ZPN and ZPC subdomains of each monomer are separated by a long linker that interacts with the preceding ZPC and following ZPN subdomains by β-sheet complementation. The unique filament architecture suggests an assembly mechanism in which subunit incorporation could be synchronized with proteolytic cleavage of the C-terminal pro-peptide that anchors assembly-incompetent UMOD precursors to the membrane.

Publication metadata

Author(s): Stanisich JJ, Zyla DS, Afanasyev P, Xu J, Kipp A, Olinger E, Devuyst O, Pilhofer M, Boehringer D, Glockshuber R

Publication type: Article

Publication status: Published

Journal: eLife

Year: 2020

Volume: 9

Online publication date: 20/08/2020

Acceptance date: 19/08/2020

Date deposited: 14/12/2020

ISSN (electronic): 2050-084X

Publisher: eLife Sciences Publications Ltd


DOI: 10.7554/ELIFE.60265

PubMed id: 32815518


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