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TitleConformational Freedom of the LRP6 Ectodomain Is Regulated by N-glycosylation and the Binding of the Wnt Antagonist Dkk1.
Journal, issue, pagesCell Rep, Vol. 18, Issue 1, Page 32-40, Year 2017
Publish dateJan 3, 2017
AuthorsKyoko Matoba / Emiko Mihara / Keiko Tamura-Kawakami / Naoyuki Miyazaki / Shintaro Maeda / Hidenori Hirai / Samuel Thompson / Kenji Iwasaki / Junichi Takagi /
PubMed AbstractLDL-receptor-related protein 6 (LRP6) is a single-pass membrane glycoprotein with a large modular ectodomain and forms a higher order signaling platform upon binding Wnt ligands on the cell surface. ...LDL-receptor-related protein 6 (LRP6) is a single-pass membrane glycoprotein with a large modular ectodomain and forms a higher order signaling platform upon binding Wnt ligands on the cell surface. Although multiple crystal structures are available for fragments of the LRP6 ectodomain, we lack a consensus view on the overall molecular architecture of the full-length LRP6 and its dynamic aspects. Here, we used negative-stain electron microscopy to probe conformational states of the entire ectodomain of LRP6 in solution and found that the four-module ectodomain undergoes a large bending motion hinged at the junction between the second and the third modules. Importantly, the extent of inter-domain motion is modulated by evolutionarily conserved N-glycan chains proximal to the joint. We also found that the LRP6 ectodomain becomes highly compact upon complexation with the Wnt antagonist Dkk1, suggesting a potential role for the ectodomain conformational change in the regulation of receptor oligomerization and signaling.
External linksCell Rep / PubMed:28052259
MethodsEM (single particle)
Resolution21.0 Å
Structure data

EMDB-9501, PDB-5gje:
Three-dimensional reconstruction of human LRP6 ectodomain complexed with Dkk1
Method: EM (single particle) / Resolution: 21.0 Å

Chemicals

ChemComp-PO4:
PHOSPHATE ION

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-GOL:
GLYCEROL

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Wnt signaling / Wnt co-receptor / LRP6 / glycoprotein / antagonist / Dkk1 / conformational change

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