Journal: Elife / Year: 2020 Title: The cryo-EM structure of the human uromodulin filament core reveals a unique assembly mechanism. Authors: Jessica J Stanisich / Dawid S Zyla / Pavel Afanasyev / Jingwei Xu / Anne Kipp / Eric Olinger / Olivier Devuyst / Martin Pilhofer / Daniel Boehringer / Rudi Glockshuber / Abstract: 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 ...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.
History
Deposition
Jul 15, 2020
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Header (metadata) release
Sep 2, 2020
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Map release
Sep 2, 2020
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Update
Sep 2, 2020
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Current status
Sep 2, 2020
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Model: Homemade / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: LACEY / Support film - Film thickness: 3.0 nm
Vitrification
Cryogen name: ETHANE-PROPANE / Chamber humidity: 95 % / Chamber temperature: 282 K / Instrument: FEI VITROBOT MARK IV Details: 3.5 ul sample, 30 s wait time, 0.5 s drain time, 13.5 s blotting from the back.
Details
individual, isolated fibers
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Number grids imaged: 2 / Number real images: 9543 / Average exposure time: 6.0 sec. / Average electron dose: 45.0 e/Å2 / Details: Data was joined from two sessions
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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