New structural insight of C-terminal region of Syntenin-1, enhancing the molecular dimerization and inhibitory function related on Syndecan-4 signaling

Youngsil Choi, Ji Hye Yun, Jiho Yoo, Inhwan Lee, Heeyoun Kim, Hye Nam Son, In San Kim, Ho Sup Yoon, Pascale Zimmermann, John R. Couchman, Hyun Soo Cho, Eok Soo Oh, Weontae Lee

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Abstract

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.

Original languageEnglish
Article number36818
JournalScientific reports
Volume6
DOIs
Publication statusPublished - 2016 Nov 10

All Science Journal Classification (ASJC) codes

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    Choi, Y., Yun, J. H., Yoo, J., Lee, I., Kim, H., Son, H. N., Kim, I. S., Yoon, H. S., Zimmermann, P., Couchman, J. R., Cho, H. S., Oh, E. S., & Lee, W. (2016). New structural insight of C-terminal region of Syntenin-1, enhancing the molecular dimerization and inhibitory function related on Syndecan-4 signaling. Scientific reports, 6, [36818]. https://doi.org/10.1038/srep36818