Related Experiment Video
Updated: Jul 20, 2025
05:48
Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
Published on: January 2, 2018
7.6K
Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active
Lukas Grätz1, Maria Kowalski-Jahn1, Magdalena M Scharf1
1Karolinska Institutet, Dept. Physiology & Pharmacology, Sec. Receptor Biology & Signaling, Biomedicum, S-17165, Stockholm, Sweden.
Nature Communications
|July 29, 2023
Summary
Frizzled receptors (FZD) signal through Disheveled (DVL) or G proteins. Our study reveals conserved residues in FZD5 are crucial for selecting signaling pathways, suggesting conformational changes dictate transducer choice.
Area of Science:
- Molecular Biology
- Cell Signaling
- Structural Biology
Background:
- Frizzled (FZD) receptors, a class of G protein-coupled receptors (GPCRs), are crucial for various biological processes.
- FZD receptors signal via Disheveled (DVL) or heterotrimeric G proteins, but the mechanisms of pathway selection remain unclear.
Purpose of the Study:
- To investigate the role of conserved residues in FZD5 in specifying signaling pathways.
- To understand how FZD receptor structure influences signal transduction outcomes.
Main Methods:
- Structure-driven mutagenesis of FZD5.
- Extensive functional signaling assays.
- Comparative molecular dynamics simulations of FZD5 variants.
Main Results:
- Conserved residues in FZD5 are essential for signal pathway selection.
- FZD5 and related FZD receptors preferentially couple to DVL over G proteins.
- Distinct active-state conformational changes in FZD receptors determine transducer selectivity.
Conclusions:
- Frizzled receptors utilize specific micro-switches to select signaling pathways.
- Conformational dynamics of FZD receptors are critical for defining their interaction with downstream signaling partners.
Related Concept Videos
01:41Non-Canonical Wnt Signaling Pathways
7.3K
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
7.3K
01:30Transducer Mechanism: G Protein–Coupled Receptors
2.1K
G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
GPCRs are also called heptahelical,...
2.1K
02:54Canonical Wnt Signaling Pathway
8.8K
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
8.8K
02:33Hedgehog Signaling Pathway
7.4K
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
7.4K
01:19Membrane Asymmetry Regulating Transporters
4.6K
Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
4.6K
03:14Notch Signaling Pathway
4.3K
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
4.3K