The PDZ domain-containing scaffold protein, syntenin-1, binds to the transmembrane proteoglycan, syndecan-4, but the molecular mechanism/function of this interaction are unknown. Crystal structure analysis of syntenin-1/syndecan-4 cytoplasmic domains revealed that syntenin-1 forms a symmetrical pair of dimers anchored by a syndecan-4 dimer. The syndecan-4 cytoplasmic domain is a compact intertwined dimer with a symmetrical clamp shape and two antiparallel strands forming a cavity within the dimeric twist. The PDZ2 domain of syntenin-1 forms a direct antiparallel interaction with the syndecan-4 cytoplasmic domain, inhibiting the functions of syndecan-4 such as focal adhesion formation. Moreover, C-terminal region of syntenin-1 reveals an essential role for enhancing the molecular homodimerization. Mutation of key syntenin-1 residues involved in the syndecan-4 interaction or homodimer formation abolishes the inhibitory function of syntenin-1, as does deletion of the homodimerization-related syntenin-1 C-terminal domain. Syntenin-1, but not dimer-formation-incompetent mutants, rescued the syndecan-4-mediated inhibition of migration and pulmonary metastasis by B16F10 cells. Therefore, we conclude that syntenin-1 negatively regulates syndecan-4 function via oligomerization and/or syndecan-4 interaction, impacting cytoskeletal organization and cell migration.
Bibliographical noteFunding Information:
This research was supported by Mid-career Researcher Program (NRF-2013R1A2A2A01068963 to W.L.) and by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (No. 2010- 0026103 to E.S.O.) and by the Translational Research Center for Protein Function Control (2016R1A5A1004694). This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (No. NRF-2016R1A5A1010764) and President's postdoctoral fellowship (NRF- 2016R1A6A3A04010213). J.R.C. is supported by The Danish National Research Foundation, Danish Medical Research Council, and Novo Nordisk Fonden. The authors thank Prof. Kurt W?thrich (ETH, Z?rich) for fruitful discussions.
© The Author(s) 2016.
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