Details

Autor(en) / Beteiligte

• Chen, Shuo
• Bubeck, Doryen
• MacDonald, Bryan T.
• Liang, Wen-Xue
• Mao, Jian-Hua
• Malinauskas, Tomas
• Llorca, Oscar
• Aricescu, A. Radu
• Siebold, Christian
• He, Xi
• Jones, E. Yvonne

Titel

Structural and Functional Studies of LRP6 Ectodomain Reveal a Platform for Wnt Signaling

Ist Teil von

• Developmental cell, 2011-11, Vol.21 (5), p.848-861

Ort / Verlag

Cambridge, MA: Elsevier Inc

Erscheinungsjahr

2011

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• LDL-receptor-related protein 6 (LRP6), alongside Frizzled receptors, transduces Wnt signaling across the plasma membrane. The LRP6 ectodomain comprises four tandem β-propeller–EGF-like domain (PE) pairs that harbor binding sites for Wnt morphogens and their antagonists including Dickkopf 1 (Dkk1). To understand how these multiple interactions are integrated, we combined crystallographic analysis of the third and fourth PE pairs with electron microscopy (EM) to determine the complete ectodomain structure. An extensive inter-pair interface, conserved for the first-to-second and third-to-fourth PE interactions, contributes to a compact platform-like architecture, which is disrupted by mutations implicated in developmental diseases. EM reconstruction of the LRP6 platform bound to chaperone Mesd exemplifies a binding mode spanning PE pairs. Cellular and binding assays identify overlapping Wnt3a- and Dkk1-binding surfaces on the third PE pair, consistent with steric competition, but also suggest a model in which the platform structure supports an interplay of ligands through multiple interaction sites. ► Crystal structure of LRP6 tandem repeats defines domain interfaces ► Electron microscopy reconstruction of LRP6 reveals a compact platform-like shape ► Wnt3a and Dkk1 share overlapping binding surfaces on the top face of LRP6 P3 ► Our platform model provides a structural basis for disease-associated LRP mutations