Elucidating the structural features of the signaling molecule reelin by x-ray crystallography

Introduction Reelin, a gigantic extracellular glycoprotein, plays a central role in cortical layer formation during mammalian brain development. Reelin was originally identified as a gene product absent in reeler mice exhibiting malformations of the cerebral cortex. Reelin acts on migrating neuronal precursors, and regulates correct cell positioning in the cortex and other brain structures. It is now accepted that reelin binds to the LDLR family receptors such as ApoER2 or VLDLR on neurons and initiates a signaling cascade involving phosphorylation of the adaptor molecule Dab-1. Reelin is a modular protein and has a characteristic repeat structure termed as the reelin repeat. Reelin contains eight repeats in total, and each repeat comprises a central epidermal growth factor (EGF) module flanked by two homologous subrepeats of 150-190 amino acids. The EGF-like module is ubiquitous among extracellular proteins, but the two subrepeats are unique to reelin and fail to show any sequence similarities to other protein families. Thus, the structural data were not at all available for the reelin repeat as well as the full-length reelin molecule. In this study, we tried to elucidate the structural features of the reelin molecule by x-ray crystallography.