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Related Concept Videos

Hedgehog Signaling Pathway02:33

Hedgehog Signaling Pathway

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...
Hedgehog Signaling Pathway02:33

Hedgehog Signaling Pathway

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...
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
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Notch Signaling Pathway03:14

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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.
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Notch Signaling Pathway03:14

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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.
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Proteoglycans are extensively glycosylated proteins, commonly found in the extracellular matrix, interwoven with collagen fibers. Hyaline cartilage, the most common type of cartilage in the body, consists of short and dispersed collagen fibers associated with large amounts of proteoglycans. These proteoglycans have long negative charges that attract cations, which in turn attract water molecules. This influx of ions and water molecules swells up the proteoglycan like a water-soaked gel that can...

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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
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Structural insights into proteoglycan-shaped Hedgehog signaling.

Daniel M Whalen1, Tomas Malinauskas, Robert J C Gilbert

  • 1Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|September 25, 2013
PubMed
Summary

Glycosaminoglycans (GAGs) bind Hedgehog (Hh) morphogens at a novel site, influencing Hh gradient formation and multimerization. This finding explains disease correlations and reveals a new Hh signaling modulation mechanism.

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Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Structural Biology

Background:

  • Hedgehog (Hh) morphogens are crucial for embryonic development and adult homeostasis.
  • Hh signaling pathways are regulated by cell surface receptors, including proteoglycan glycosaminoglycan (GAG) chains.
  • GAGs influence Hh gradient formation and signal transduction.

Purpose of the Study:

  • To determine the crystal structures of Sonic Hh complexes with heparin and chondroitin sulfate.
  • To identify the interaction sites and mechanisms of GAG binding to Hh.
  • To elucidate the role of GAGs in Hh multimerization and signaling modulation.

Main Methods:

  • X-ray crystallography of Sonic Hh-GAG complexes.
  • Site-directed mutagenesis and binding assays.
  • Analytical ultracentrifugation.

Main Results:

  • A novel GAG-binding site on Hh proteins was identified, conserved across all Hh family members.
  • This GAG-binding site involves residues previously linked to developmental diseases.
  • GAG binding promotes Hh multimerization and modulates interactions with other Hh pathway proteins.

Conclusions:

  • The findings provide a mechanistic link between GAGs, Hh gradient formation, and developmental diseases.
  • GAGs act as a key regulator of Hh signaling by influencing Hh multimerization and protein interactions.