Frizzleds are dynamic, molecular machines

Frizzleds are dynamic, molecular machines


<div data-thumb="https://scx1.b-cdn.net/csz/news/tmb/2021/frizzleds-are-dynamic.jpg" data-src="https://scx2.b-cdn.net/gfx/news/hires/2021/frizzleds-are-dynamic.jpg" data-sub-html="Fig. 1. MD of FZD6 and receptor model with amber codon placement.(A) Superimposition of the FZD6 model (blue) and inactive SMO (gray; PDB ID: 5L7D). Disulfide bridges are shown as sticks. The dotted rectangles mark the extended linker region, which differs between these two structures. (B) A closer view to the FZD6 model. Amino acid residues selected for the point mutations are marked as sticks. Color code is as follows: red, oxygen; dark blue, nitrogen; light blue, carbon; yellow, sulfur. (C) The CRD movements in the MD simulation. The receptor cores are shown as cartoon and CRDs as solid surfaces. Colored arrows mark the locations of the N termini of each conformation cluster. Cumulative percentage of the time of coverage for each position cluster in the MD (absolute percentage for each cluster in parentheses). (D) Protein backbone root mean square deviations (RMSDs) of the receptor core (amino acids 160 to 511) and the CRD (amino acids 1 to 130) plotted as a continuous simulation trajectory. Dotted lines mark the independent simulation replicas. Thick blue traces indicate the moving average smoothed over a 2-ns window, and thin traces indicate the raw data.”>

6 and receptor model with amber codon placement.(A) Superimposition of the FZD6 model (blue) and inactive SMO (gray; PDB ID: 5L7D). Disulfide bridges are shown as sticks. The dotted rectangles mark the extended linker region, which differs between these two structures. (B) A closer view to the FZD6 model. Amino acid residues selected for the point mutations are marked as sticks. Color code is as follows: red, oxygen; dark blue, nitrogen; light blue, carbon; yellow, sulfur. (C) The CRD movements in the MD simulation. The receptor cores are shown as cartoon and CRDs as solid surfaces. Colored arrows mark the locations of the N termini of each conformation cluster. Cumulative percentage of the time of coverage for each position cluster in the MD (absolute percentage for each cluster in parentheses). (D) Protein backbone root mean square deviations (RMSDs) of the receptor core (amino acids 160 to 511) and the CRD (amino acids 1 to 130) plotted as a continuous simulation trajectory. Dotted lines mark the independent simulation replicas. Thick blue traces indicate the moving average smoothed over a 2-ns window, and thin traces indicate the raw data.” width=”800″ height=”530″/>
Fig. 1. MD of FZD6 and receptor model with amber codon placement.(A) Superimposition of the FZD6 model (blue) and inactive SMO (gray; PDB ID: 5L7D). Disulfide bridges are shown as sticks. The dotted rectangles mark the extended linker region, which differs between these two structures. (B) A closer view to the FZD6 model. Amino acid residues selected for the point mutations are marked as sticks. Color code is as follows: red, oxygen; dark blue, nitrogen; light blue, carbon; yellow, sulfur. (C) The CRD movements in the MD simulation. The receptor cores are shown as cartoon and CRDs as solid surfaces. Colored arrows mark the locations of the N termini of each conformation cluster. Cumulative percentage of the time of coverage for each position cluster in the MD (absolute percentage for each cluster in parentheses). (D) Protein backbone root mean square deviations (RMSDs) of the receptor core (amino acids 160 to 511) and the CRD (amino acids 1 to 130) plotted as a continuous simulation trajectory. Dotted lines mark the independent simulation replicas. Thick blue traces indicate the moving average smoothed over a 2-ns window, and thin traces indicate the raw data.

Maria Kowalski-Jahn and Hannes Schihada, two postdocs in the Schulte laboratory, have used a novel technology of fluorescently labeling receptors with a minimally invasive technique and detecting structural rearrangements in a receptor molecule in living cells. These experiments pinpointed how FZDs respond to WNT stimulation by conformational changes in the extracellular domain of the receptor. In contrast to what was previously surmised, but in line with several previous publications by the Schulte laboratory, these findings underline that WNT stimulation elicits conformational rearrangements in their receptors. These new insights into FZD dynamics present the basis for a continued mechanism-based drug discovery process to target FZDs for therapy.

Cell surface receptors are essential to transmit information from the outside of the cell to the inside to accomplish a physiological adaptation in response to the perceived signal. This basic concept of cellular communication can be exploited by therapeutic intervention using drugs that either mimic the bodily molecule activating the receptor (agonists) or interfere with binding of the bodily molecule as so-called antagonists. Irrespectively, the dynamic process of receptor activation can only be targeted if it is understood in its basic details. The Schulte laboratory works on Class F G protein-coupled receptors including Frizzleds, which are seen as attractive drug targets for example for cancer therapy. So far, however, the molecular underpinnings of ligand (WNT)-induced FZD activation remains obscure.

This study is published in Science Advances.


New opportunity for cancer drug development


More information:
Maria Kowalski-Jahn et al, Frizzled BRET sensors based on bioorthogonal labeling of unnatural amino acids reveal WNT-induced dynamics of the cysteine-rich domain, Science Advances (2021). DOI: 10.1126/sciadv.abj7917

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Frizzleds are dynamic, molecular machines (2021, November 11)
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