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

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...

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Bibliographic Details
Published in:The EMBO journal 2006-08, Vol.25 (15), p.3675-3683
Main Authors: Nogi, Terukazu, Yasui, Norihisa, Hattori, Mitsuharu, Iwasaki, Kenji, Takagi, Junichi
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Brain
brain development
Cell Adhesion Molecules, Neuronal - chemistry
Cell Adhesion Molecules, Neuronal - genetics
Cell Adhesion Molecules, Neuronal - metabolism
CHO Cells
Cricetinae
Cricetulus
Crystal structure
Crystallography, X-Ray
Dab1
EGF module
Extracellular Matrix Proteins - chemistry
Extracellular Matrix Proteins - genetics
Extracellular Matrix Proteins - metabolism
Glycoproteins
Mice
Microscopy, Electron - methods
Models, Biological
Molecular Sequence Data
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
neuronal migration
Neurons
Prenatal development
Protein Conformation
Protein Structure, Tertiary
reelin
Scientific imaging
Sequence Alignment
Serine Endopeptidases - chemistry
Serine Endopeptidases - genetics
Serine Endopeptidases - metabolism
Signal Transduction
Tomography - methods
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Summary: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.
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7601240