7zaw

From Proteopedia

(Difference between revisions)

Current revision

GPC3-Unc5D octamer structure and role in cell migration

Structural highlights

7zaw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.58Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GPC3_HUMAN Nephroblastoma;Simpson-Golabi-Behmel syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

GPC3_HUMAN Cell surface proteoglycan (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity).[UniProtKB:Q6V9Y8][UniProtKB:Q8CFZ4]^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.

GPC3-Unc5 receptor complex structure and role in cell migration.,Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E Cell. 2022 Oct 13;185(21):3931-3949.e26. doi: 10.1016/j.cell.2022.09.025. PMID:36240740^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ De Cat B, Muyldermans SY, Coomans C, Degeest G, Vanderschueren B, Creemers J, Biemar F, Peers B, David G. Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. J Cell Biol. 2003 Nov 10;163(3):625-35. doi: 10.1083/jcb.200302152. PMID:14610063 doi:http://dx.doi.org/10.1083/jcb.200302152
↑ Capurro MI, Shi W, Sandal S, Filmus J. Processing by convertases is not required for glypican-3-induced stimulation of hepatocellular carcinoma growth. J Biol Chem. 2005 Dec 16;280(50):41201-6. doi: 10.1074/jbc.M507004200. Epub 2005 , Oct 14. PMID:16227623 doi:http://dx.doi.org/10.1074/jbc.M507004200
↑ Davoodi J, Kelly J, Gendron NH, MacKenzie AE. The Simpson-Golabi-Behmel syndrome causative glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26. Proteomics. 2007 Jun;7(13):2300-10. PMID:17549790 doi:10.1002/pmic.200600654
↑ Capurro M, Martin T, Shi W, Filmus J. Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling. J Cell Sci. 2014 Apr 1;127(Pt 7):1565-75. doi: 10.1242/jcs.140871. Epub 2014 Feb , 4. PMID:24496449 doi:http://dx.doi.org/10.1242/jcs.140871
↑ Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E. GPC3-Unc5 receptor complex structure and role in cell migration. Cell. 2022 Oct 13;185(21):3931-3949.e26. doi: 10.1016/j.cell.2022.09.025. PMID:36240740 doi:http://dx.doi.org/10.1016/j.cell.2022.09.025

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7zaw"

@@ Line 11: / Line 11: @@
 [https://www.uniprot.org/uniprot/GPC3_HUMAN GPC3_HUMAN] Nephroblastoma;Simpson-Golabi-Behmel syndrome. The disease is caused by variants affecting the gene represented in this entry.
 == Function ==
-[https://www.uniprot.org/uniprot/GPC3_HUMAN GPC3_HUMAN] Cell surface proteoglycan that bears heparan sulfate (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity).[UniProtKB:Q6V9Y8][UniProtKB:Q8CFZ4]<ref>PMID:14610063</ref> <ref>PMID:16227623</ref> <ref>PMID:17549790</ref> <ref>PMID:24496449</ref>
+[https://www.uniprot.org/uniprot/GPC3_HUMAN GPC3_HUMAN] Cell surface proteoglycan (PubMed:14610063). Negatively regulates the hedgehog signaling pathway when attached via the GPI-anchor to the cell surface by competing with the hedgehog receptor PTC1 for binding to hedgehog proteins (By similarity). Binding to the hedgehog protein SHH triggers internalization of the complex by endocytosis and its subsequent lysosomal degradation (By similarity). Positively regulates the canonical Wnt signaling pathway by binding to the Wnt receptor Frizzled and stimulating the binding of the Frizzled receptor to Wnt ligands (PubMed:16227623, PubMed:24496449). Positively regulates the non-canonical Wnt signaling pathway (By similarity). Binds to CD81 which decreases the availability of free CD81 for binding to the transcriptional repressor HHEX, resulting in nuclear translocation of HHEX and transcriptional repression (By similarity). Inhibits the dipeptidyl peptidase activity of DPP4 (PubMed:17549790). Plays a role in limb patterning and skeletal development by controlling the cellular response to BMP4 (By similarity). Modulates the effects of growth factors BMP2, BMP7 and FGF7 on renal branching morphogenesis (By similarity). Required for coronary vascular development (By similarity). Plays a role in regulating cell movements during gastrulation (By similarity).[UniProtKB:Q6V9Y8][UniProtKB:Q8CFZ4]<ref>PMID:14610063</ref> <ref>PMID:16227623</ref> <ref>PMID:17549790</ref> <ref>PMID:24496449</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

7zaw

From Proteopedia

Current revision

GPC3-Unc5D octamer structure and role in cell migration

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox