National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
1R01DK115728
United States
Howard Hughes Medical Institute (HHMI)
United States
Department of Energy (DOE, United States)
DE-AC02-76SF00515
United States
Citation
Journal: Elife / Year: 2020 Title: Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling. Authors: Naotaka Tsutsumi / Somnath Mukherjee / Deepa Waghray / Claudia Y Janda / Kevin M Jude / Yi Miao / John S Burg / Nanda Gowtham Aduri / Anthony A Kossiakoff / Cornelius Gati / K Christopher Garcia / Abstract: Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd remains poorly understood. ...Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd remains poorly understood. Here we report the structure of an unliganded human Fzd5 determined by single-particle cryo-EM at 3.7 Å resolution, with the aid of an antibody chaperone acting as a fiducial marker. We also analyzed the topology of low-resolution XWnt8/Fzd5 complex particles, which revealed extreme flexibility between the Wnt/Fzd-CRD and the Fzd-TM regions. Analysis of Wnt/β-catenin signaling in response to Wnt3a versus a 'surrogate agonist' that cross-links Fzd to LRP6, revealed identical structure-activity relationships. Thus, canonical Wnt/β-catenin signaling appears to be principally reliant on ligand-induced Fzd/LRP6 heterodimerization, versus the allosteric mechanisms seen in structurally analogous class A G protein-coupled receptors, and Smoothened. These findings deepen our mechanistic understanding of Wnt signal transduction, and have implications for harnessing Wnt agonism in regenerative medicine.
History
Deposition
May 7, 2020
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Header (metadata) release
Aug 19, 2020
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Map release
Aug 19, 2020
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Update
Aug 19, 2020
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Current status
Aug 19, 2020
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
EMPIAR-10507 (Title: Structure of human Frizzled5 by fiducial-assisted cryo-EM Data size: 6.0 TB Data #1: Unaligned dark-subtracted TIFF movies with a gain reference for the 3D reconstruction of EMD-21927. [micrographs - multiframe])
Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 281 K / Instrument: LEICA EM GP / Details: 5s blotting.
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Electron microscopy
Microscope
FEI TITAN KRIOS
Specialist optics
Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recording
Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 10898 / Average exposure time: 0.1225 sec. / Average electron dose: 50.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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