Background:The physiological role of Reelin proteolysis is largely uncharacterized. Results: An "uncleavable" Reelin mutant remains active for a long time, and the cleaved Reelin fragment localizes differently than full-length Reelin. Conclusion: Extracellular and intracellular Reelin cleavage is required for halting downstream signaling and transport of the cleaved product. Significance: Inhibition of Reelin cleavage will be beneficial for treating neuropsychiatric diseases.

Edited by Jesus AvilaKeywords: Reelin Brain Protease ADAMTS Processing a b s t r a c t Reelin is a glycoprotein essential for brain development and functions. Reelin is subject to specific proteolysis at two distinct (N-t and C-t) sites, and these cleavages significantly diminish Reelin activity. The decrease of Reelin activity is detrimental for brain function, but the protease that catalyzes specific cleavage of Reelin remains elusive. Here we found that a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4) cleaves Reelin in an isoform-specific manner. Among ADAMTS-4 isoforms, p50 cleaves the N-t site only, while p75 cleaves both sites. This is the first report identifying a protease that can specifically cleave Reelin.