Structural basis of syndecan-4 phosphorylation as a molecular switch to regulate signaling

Bon Kyung Koo, Young Sang Jung, Joon Shin, Innoc Han, Eva Mortier, Pascale Zimmermann, James R. Whiteford, John R. Couchman, Eok Soo Oh, Weontae Lee

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The syndecan transmembrane proteoglycans are involved in the organization of the actin cytoskeleton and have important roles as cell surface receptors during cell-matrix interactions. We have shown that the syndecan-4 cytoplasmic domain (4L) forms oligomeric complexes that bind to and stimulate PKCα activity in the presence of PtdIns(4,5)P2, emphasizing the importance of multimerization in the regulation of PKCα activation. Oligomerization of the cytoplasmic domain of syndecan-4 is regulated either positively by PtdIns(4,5)P2 or negatively by phosphorylation of serine 183. Phosphorylation results in reduced PKCα activity by inhibiting PtdIns(4,5)P2-dependent oligomerization of the syndecan-4 cytoplasmic domain. Data from NMR and gel-filtration chromatography show that the phosphorylated cytoplasmic domain (p-4L) exists as a dimer, similar to 4L, but not as higher-order oligomers. NMR analysis showed that the overall conformation of p-4L is a compact intertwined dimer with an unusually symmetric clamp shape, and its molecular surface is mostly positively charged. The two parallel strands form a cavity in the center of the dimeric twist. An especially marked effect of phosphorylation of the syndecan-4 cytoplasmic domain is a dramatic conformational change near the C2 region that ablates an interaction site with the PDZ domain of syntenin. Wound healing studies further suggest that syndecan-4 phosphorylation might influence cell migration behavior. We conclude that the phosphorylation (Ser183) of syndecan-4 can play a critical role as a molecular switch to regulate its functions through conformational change.

Original languageEnglish
Pages (from-to)651-663
Number of pages13
JournalJournal of Molecular Biology
Volume355
Issue number4
DOIs
Publication statusPublished - 2006 Jan 27

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Syndecan-4
Phosphatidylinositol 4,5-Diphosphate
Phosphorylation
Syntenins
Syndecans
PDZ Domains
Cell Surface Receptors
Proteoglycans
Actin Cytoskeleton
Cell Communication
Wound Healing
Serine
Cell Movement
Gel Chromatography

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

Cite this

Koo, Bon Kyung ; Jung, Young Sang ; Shin, Joon ; Han, Innoc ; Mortier, Eva ; Zimmermann, Pascale ; Whiteford, James R. ; Couchman, John R. ; Oh, Eok Soo ; Lee, Weontae. / Structural basis of syndecan-4 phosphorylation as a molecular switch to regulate signaling. In: Journal of Molecular Biology. 2006 ; Vol. 355, No. 4. pp. 651-663.
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Koo, BK, Jung, YS, Shin, J, Han, I, Mortier, E, Zimmermann, P, Whiteford, JR, Couchman, JR, Oh, ES & Lee, W 2006, 'Structural basis of syndecan-4 phosphorylation as a molecular switch to regulate signaling', Journal of Molecular Biology, vol. 355, no. 4, pp. 651-663. https://doi.org/10.1016/j.jmb.2005.09.087

Structural basis of syndecan-4 phosphorylation as a molecular switch to regulate signaling. / Koo, Bon Kyung; Jung, Young Sang; Shin, Joon; Han, Innoc; Mortier, Eva; Zimmermann, Pascale; Whiteford, James R.; Couchman, John R.; Oh, Eok Soo; Lee, Weontae.

In: Journal of Molecular Biology, Vol. 355, No. 4, 27.01.2006, p. 651-663.

Research output: Contribution to journalArticle

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AU - Koo, Bon Kyung

AU - Jung, Young Sang

AU - Shin, Joon

AU - Han, Innoc

AU - Mortier, Eva

AU - Zimmermann, Pascale

AU - Whiteford, James R.

AU - Couchman, John R.

AU - Oh, Eok Soo

AU - Lee, Weontae

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AB - The syndecan transmembrane proteoglycans are involved in the organization of the actin cytoskeleton and have important roles as cell surface receptors during cell-matrix interactions. We have shown that the syndecan-4 cytoplasmic domain (4L) forms oligomeric complexes that bind to and stimulate PKCα activity in the presence of PtdIns(4,5)P2, emphasizing the importance of multimerization in the regulation of PKCα activation. Oligomerization of the cytoplasmic domain of syndecan-4 is regulated either positively by PtdIns(4,5)P2 or negatively by phosphorylation of serine 183. Phosphorylation results in reduced PKCα activity by inhibiting PtdIns(4,5)P2-dependent oligomerization of the syndecan-4 cytoplasmic domain. Data from NMR and gel-filtration chromatography show that the phosphorylated cytoplasmic domain (p-4L) exists as a dimer, similar to 4L, but not as higher-order oligomers. NMR analysis showed that the overall conformation of p-4L is a compact intertwined dimer with an unusually symmetric clamp shape, and its molecular surface is mostly positively charged. The two parallel strands form a cavity in the center of the dimeric twist. An especially marked effect of phosphorylation of the syndecan-4 cytoplasmic domain is a dramatic conformational change near the C2 region that ablates an interaction site with the PDZ domain of syntenin. Wound healing studies further suggest that syndecan-4 phosphorylation might influence cell migration behavior. We conclude that the phosphorylation (Ser183) of syndecan-4 can play a critical role as a molecular switch to regulate its functions through conformational change.

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