Drosophila OTK Is a Glycosaminoglycan-Binding Protein with High Conformational Flexibility

The transmembrane protein OTK plays an essential role in plexin and Wnt signaling during Drosophila development. We have determined a crystal structure of the last three domains of the OTK ectodomain and found that OTK shows high conformational flexibility resulting from mobility at the interdomain interfaces. We failed to detect direct binding between Drosophila Plexin A (PlexA) and OTK, which was suggested previously. We found that, instead of PlexA, OTK directly binds semaphorin 1a. Our binding analyses further revealed that glycosaminoglycans, heparin and heparan sulfate, are ligands for OTK and thus may play a role in the Sema1a-PlexA axon guidance system. [Display omitted] •Drosophila OTK exhibits extensive interdomain flexibility•OTK interacts with glycosaminoglycans•OTK directly interacts with Sema1a but not PlexA Drosophila OTK is a single-spanning transmembrane protein that plays essential roles in development and reproduction. Here, Rozbesky et al. report on the crystal structure of the last three domains of the OTK ectodomain. Binding studies highlight that OTK directly binds glycosaminoglycans and an axon guidance molecule, semaphorin 1a.