Reelin molecules assemble together to form a large protein complex, which is inhibited by the function-blocking CR-50 antibody

Reelin is a key mediator of ordered neuronal alignment in the brain. Here, we demonstrate that Reelin molecules assemble with each other to form a hug e protein complex both in vitro and in vivo. The Reelin-Reelin interaction dearly is inhibited by the function-blocking anti-Reelin antibody, CR-50, a t a concentration known to inhibit Reelin function. This assembly is mediat ed by electrostatic interaction of the CR-50 epitope region. Recombinant CR -50 epitope fragments spontaneously constitute a soluble, string-like homop olymer with a regularly repeated structure composed of more than 40 monomer s. Mutated Reelin, which lacks the CR-50 epitope region, cannot form a homo polymer and fails to induce efficient tyrosine phosphorylation of Disabled 1 (Dab1). which should occur to transduce the Reelin signal. These data sug gest that Reelin exerts its biological function by composing a large protei n assembly driven by the CR-50 epitope region, proposing a novel model of t he Reelin signaling in neurodevelopment.