| Structural highlights
Function
[DISP_DROME] Segment polarity protein which functions in hedgehog (Hh) signaling. Regulates the trafficking and the release of cholesterol-modified hedgehog protein from cells of the posterior compartment (P cells) and is hence required for the effective production of the Hh signal.[1] [2] [3] [HH_DROME] Intercellular signal essential for a variety of patterning events during development. Establishes the anterior-posterior axis of the embryonic segments and patterns the larval imaginal disks. Binds to the patched (ptc) receptor, which functions in association with smoothened (smo), to activate the transcription of target genes wingless (wg), decapentaplegic (dpp) and ptc. In the absence of hh, ptc represses the constitutive signaling activity of smo through fused (fu).[4] [5] [6] [7] The hedgehog protein N-product constitutes the active species in both local and long-range signaling, whereas the C-terminal product has no signaling activity. It acts as a morphogen, and diffuses long distances despite its lipidation. Heparan sulfate proteoglycans of the extracellular matrix play an essential role in diffusion. Lipophorin is required for diffusion, probably by acting as vehicle for its movement, explaining how it can spread over long distances despite its lipidation.[8] [9] [10] [11] The hedgehog protein C-product, which mediates the autocatalytic activity, has no signaling activity.[12] [13] [14] [15]
Publication Abstract from PubMed
The Hedgehog (Hh) signaling pathway controls embryonic development and adult tissue homeostasis in multicellular organisms. In Drosophila melanogaster, the pathway is primed by secretion of a dually lipid-modified morphogen, Hh, a process dependent on a membrane-integral protein Dispatched. Although Dispatched is a critical component of the pathway, the structural basis of its activity has, so far, not been described. Here, we describe a cryo-electron microscopy structure of the D. melanogaster Dispatched at 3.2-A resolution. The ectodomains of Dispatched adopt an open conformation suggestive of a receptor-chaperone role. A three-dimensional reconstruction of Dispatched bound to Hh confirms the ability of Dispatched to bind Hh but using a unique mode distinct from those previously observed in structures of Hh complexes. The structure may represent the state of the complex that precedes shedding of Hh from the surface of the morphogen-releasing cell.
Cryo-EM structure of the Hedgehog release protein Dispatched.,Cannac F, Qi C, Falschlunger J, Hausmann G, Basler K, Korkhov VM Sci Adv. 2020 Apr 15;6(16):eaay7928. doi: 10.1126/sciadv.aay7928. eCollection, 2020 Apr. PMID:32494603[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ, Basler K. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell. 1999 Dec 23;99(7):803-15. PMID:10619433
- ↑ Ma Y, Erkner A, Gong R, Yao S, Taipale J, Basler K, Beachy PA. Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell. 2002 Oct 4;111(1):63-75. doi: 10.1016/s0092-8674(02)00977-7. PMID:12372301 doi:https://dx.doi.org/10.1016/s0092-8674(02)00977-7
- ↑ Gallet A, Rodriguez R, Ruel L, Therond PP. Cholesterol modification of hedgehog is required for trafficking and movement, revealing an asymmetric cellular response to hedgehog. Dev Cell. 2003 Feb;4(2):191-204. doi: 10.1016/s1534-5807(03)00031-5. PMID:12586063 doi:https://dx.doi.org/10.1016/s1534-5807(03)00031-5
- ↑ Tashiro S, Michiue T, Higashijima S, Zenno S, Ishimaru S, Takahashi F, Orihara M, Kojima T, Saigo K. Structure and expression of hedgehog, a Drosophila segment-polarity gene required for cell-cell communication. Gene. 1993 Feb 28;124(2):183-9. PMID:8166882
- ↑ Lee JJ, von Kessler DP, Parks S, Beachy PA. Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell. 1992 Oct 2;71(1):33-50. PMID:1394430
- ↑ Tabata T, Eaton S, Kornberg TB. The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Genes Dev. 1992 Dec;6(12B):2635-45. PMID:1340474
- ↑ Lee JD, Kraus P, Gaiano N, Nery S, Kohtz J, Fishell G, Loomis CA, Treisman JE. An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. Dev Biol. 2001 May 1;233(1):122-36. PMID:11319862 doi:https://dx.doi.org/10.1006/dbio.2001.0218
- ↑ Tashiro S, Michiue T, Higashijima S, Zenno S, Ishimaru S, Takahashi F, Orihara M, Kojima T, Saigo K. Structure and expression of hedgehog, a Drosophila segment-polarity gene required for cell-cell communication. Gene. 1993 Feb 28;124(2):183-9. PMID:8166882
- ↑ Lee JJ, von Kessler DP, Parks S, Beachy PA. Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell. 1992 Oct 2;71(1):33-50. PMID:1394430
- ↑ Tabata T, Eaton S, Kornberg TB. The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Genes Dev. 1992 Dec;6(12B):2635-45. PMID:1340474
- ↑ Lee JD, Kraus P, Gaiano N, Nery S, Kohtz J, Fishell G, Loomis CA, Treisman JE. An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. Dev Biol. 2001 May 1;233(1):122-36. PMID:11319862 doi:https://dx.doi.org/10.1006/dbio.2001.0218
- ↑ Tashiro S, Michiue T, Higashijima S, Zenno S, Ishimaru S, Takahashi F, Orihara M, Kojima T, Saigo K. Structure and expression of hedgehog, a Drosophila segment-polarity gene required for cell-cell communication. Gene. 1993 Feb 28;124(2):183-9. PMID:8166882
- ↑ Lee JJ, von Kessler DP, Parks S, Beachy PA. Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell. 1992 Oct 2;71(1):33-50. PMID:1394430
- ↑ Tabata T, Eaton S, Kornberg TB. The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation. Genes Dev. 1992 Dec;6(12B):2635-45. PMID:1340474
- ↑ Lee JD, Kraus P, Gaiano N, Nery S, Kohtz J, Fishell G, Loomis CA, Treisman JE. An acylatable residue of Hedgehog is differentially required in Drosophila and mouse limb development. Dev Biol. 2001 May 1;233(1):122-36. PMID:11319862 doi:https://dx.doi.org/10.1006/dbio.2001.0218
- ↑ Cannac F, Qi C, Falschlunger J, Hausmann G, Basler K, Korkhov VM. Cryo-EM structure of the Hedgehog release protein Dispatched. Sci Adv. 2020 Apr 15;6(16):eaay7928. doi: 10.1126/sciadv.aay7928. eCollection, 2020 Apr. PMID:32494603 doi:https://dx.doi.org/10.1126/sciadv.aay7928
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