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Solution Structure of the N-terminal Region of Dkk4Solution Structure of the N-terminal Region of Dkk4
Structural highlights
FunctionDKK4_HUMAN Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease (By similarity). Publication Abstract from PubMedDickkopf (Dkk) family proteins are important regulators of Wnt signalling pathways, which play key roles in many essential biological processes. Here we report the first detailed structural and dynamics study of a full-length mature Dkk protein (Dkk4, residues 19-224), including determination of the first atomic resolution structure for the N-terminal cysteine-rich domain (CRD1) conserved among Dkk proteins. We discovered that CRD1 has significant structural homology to the Dkk C-terminal cysteine-rich domain (CRD2), pointing to multiple gene duplication events during Dkk family evolution. We also show that Dkk4 consists of two independent folded domains (CRD1 and CRD2) joined by a highly flexible, non-structured linker. Similarly, the N-terminal region preceding CRD1 and containing a highly conserved NXIR/K sequence motif was shown to be dynamic and highly flexible.We demonstrate that Dkk4 CRD2 mediates high-affinity binding to both the E1E2 region of LDL receptor-related protein 6 (LRP6 E1E2) and the Kremen1 (Krm1) extracellular domain. In contrast, the N-terminal region alone bound with only moderate affinity to LRP6 E1E2, consistent with binding via the conserved NXIR/K motif, but did not interact with Krm proteins. We also confirmed that Dkk and Krm family proteins function synergistically to inhibit Wnt signalling. Insights provided by our integrated structural, dynamics, interaction and functional studies have allowed us to refine the model of synergistic regulation of Wnt signalling by Dkk proteins. Our results indicate the potential for the formation of a diverse range of ternary complexes comprising Dkk, Krm and LRP5/6 proteins, allowing fine-tuning of Wnt-dependent signalling. Structural and functional analysis of Dickkopf 4 (Dkk4): new insights into Dkk evolution and regulation of Wnt signalling by Dkk and Kremen proteins.,Patel S, Barkell AM, Gupta D, Strong SL, Bruton S, Muskett FW, Addis PW, Renshaw PS, Slocombe PM, Doyle C, Clargo A, Taylor RJ, Prosser CE, Henry AJ, Robinson MK, Waters LC, Holdsworth G, Carr MD J Biol Chem. 2018 Jun 20. pii: RA118.002918. doi: 10.1074/jbc.RA118.002918. PMID:29925589[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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