Updated project metadata. Human periostin is a 78-91 kDa alternatively spliced protein belonging to the group of matricellular proteins. The protein has been implicated in extracellular matrix remodeling, tumor development, and metastasis, inflammatory diseases like atopic dermatitis, psoriasis, and asthma. The C-terminal may be alternatively spliced, but the role of the ten variants is not understood. Here we investigate the structure of the C-terminal domain containing the protein sequence encoded by the fourall exons and its interactome. Structural analysis using SAXS, CD spectroscopy, and limited proteolysis suggested that the C-terminal domain was disordered. In addition, the motif responsible for heparin-binding was mapped to an arginine-rich sequence in the conserved very C-terminal part of periostin. Co-immunoprecipitationPull-down confirmed three known interaction partners bound to the C-terminal domain of periostin and identified an additional 140 novel potential interaction partners. Nine of these have been implicated in atopic dermatitis. Based on our findings, we suggest that the C-terminal domain anchor periostin to cell surfaces and facilitates interactions between connective tissue components or other cells. We propose that the C-terminal domain is a central part of the suggested function as a multifunctional modulator of extracellular matrix stability and wound healing.