The Tweety homology (TTYH) protein family is an understudied class of membrane proteins with a unique topology consisting of five transmembrane (TM) helices and a large, heavily glycosylated, extracellular domain. With a growing number of studies indicating the implication of TTYH in neuropathological conditions, it is clear that TTYH plays an important role in the nervous system. However, the biochemical role of TTYH remains unclear, making it difficult to inform the development of disease therapeutics for this protein class. While previous studies have investigated TTYH in heterologous systems, I take advantage of C. elegans as a model organism to characterize TTYH through the identification of endogenous binding partners. C. elegans have one TTYH homolog (ceTTYH), a well studied nervous system, the capacity for genetic manipulation, and are transparent, supporting fluorescent imaging, making the nematode an ideal model organism for this study. A pull-down coupled with mass-spectroscopy revealed that syndecan (ceSDN-1) is an endogenous interactor of ceTTYH. Through biochemical and structural approaches, ceTTYH and ceSDN-1 are shown to physically interact. From a functional standpoint, ceTTYH and ceSDN-1 co-localize in C. elegans and both exhibit a locomotion defect. Furthermore, ceSDN-1 is known to play a role in axon guidance and regeneration. Based on this evidence, I hypothesize that TTYH and syndecan form a heteromultimeric complex that functions as a receptor in axon guidance and axon regeneration. To test this hypothesis, I will generate a high resolution 3D map of the complex and perform functional experiments in C. elegans to determine the physiological role of the TTYH syndecan complex. This project will inform the development of therapeutics for the numerous diseases with TTYH implication.