Clip domains are structural modules commonly found in arthropod serine proteinases and their homologs, which mediate extracellular signaling pathways of development and immunity. While little is known about their structures or functions, clip domains are proposed to be the sites for interactions of proteinases with their activators, cofactors and substrates. Here we report the solution structure of dual clip domains from Manduca sexta prophenoloxidase activating protease-2. Each domain adopts a mixed ?/? structure with a three-stranded antiparallel ?-sheet flanked by two ?-helices. The architecture provides structural insights into serine proteinase-associated clip domains for the first time. This novel fold includes a probable substrate-binding site, a putative bacteria-interacting region, and a remarkable charged surface for possible specific association with activator/cofactor. These results support the proposed roles of clip domains in prophenoloxidase activation and serve as a basis for structure-based probing of clip domain functions.