Abstract
SummaryKremen 1 and 2 have been identified as co-receptors for Dickkopf (Dkk) proteins, hallmark secreted antagonists of canonical Wnt signaling. We present here three crystal structures of the ectodomain of human Kremen1 (KRM1ECD) at resolutions between 1.9 and 3.2 Å. KRM1ECD emerges as a rigid molecule with tight interactions stabilizing a triangular arrangement of its Kringle, WSC, and CUB structural domains. The structures reveal an unpredicted homology of the WSC domain to hepatocyte growth factor. We further report the general architecture of the ternary complex formed by the Wnt co-receptor Lrp5/6, Dkk, and Krm, determined from a low-resolution complex crystal structure between β-propeller/EGF repeats (PE) 3 and 4 of the Wnt co-receptor LRP6 (LRP6PE3PE4), the cysteine-rich domain 2 (CRD2) of DKK1, and KRM1ECD. DKK1CRD2 is sandwiched between LRP6PE3 and KRM1Kringle-WSC. Modeling studies supported by surface plasmon resonance suggest a direct interaction site between Krm1CUB and Lrp6PE2.
Highlights
Signaling by Wnt morphogens is renowned for its fundamental roles in embryonic development, tissue homeostasis, and stem cell maintenance (Holstein, 2012)
The importance of intact KRM1 for normal human development and health is highlighted by the recent finding that a homozygous mutation in the ectodomain of KRM1 leads to severe ectodermal dysplasia including oligodontia (Issa et al, 2016)
We succeeded in purifying KRM1ECD complexes with DKK1fl, DKK1Linker-cysteine-rich domain 2 (CRD2), and DKK1CRD2 that were monodisperse and stable in gel filtration, indicating at least micromolar affinity
Summary
Zebisch et al describe the ectodomain structure of KREMEN 1, a receptor for Wnt antagonists of the DKK family. Apo structures and a complex with functional fragments of DKK1 and LRP6 shed light on the function of this dual-mode regulator of Wnt signaling. Highlights d The structure of the KREMEN 1 ectodomain is solved from three crystal forms d Kringle, WSC, and CUB subdomains interact tightly to form a single structural unit. 2016, Structure 24, 1599–1605 September 6, 2016 a 2016 The Authors.
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