Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography

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Abstract
The large extracellular glycoprotein reelin directs neuronal migration during brain development and plays a fundamental role in layer formation. It is composed of eight tandem repeats of an ∼380‐residue unit, termed the reelin repeat, which has a central epidermal growth factor (EGF) module flanked by two homologous subrepeats with no obvious sequence similarity to proteins of known structure. The 2.05 Å crystal structure of the mouse reelin repeat 3 reveals that the subrepeat assumes a β‐jelly‐roll fold with unexpected structural similarity to carbohydrate‐binding domains. Despite the interruption by the EGF module, the two subdomains make direct contact, resulting in a compact overall structure. Electron micrographs of a four‐domain fragment encompassing repeats 3–6, which is capable of inducing Disabled‐1 phosphorylation in neurons, show a rod‐like shape. Furthermore, a three‐dimensional molecular envelope of the fragment obtained by single‐particle tomography can be fitted with four concatenated repeat 3 atomic structures, providing the first glimpse of the structural unit for this important signaling molecule.