Structural basis of syndecan-4 phosphorylation as a molecular switch to regulate signaling.
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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, 2005, p. 651-63.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - Structural basis of syndecan-4 phosphorylation as a molecular switch to regulate signaling.
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
N1 - Keywords: Amino Acid Sequence; Animals; CHO Cells; Cell Movement; Cricetinae; Electrostatics; Enzyme Activation; Membrane Glycoproteins; Models, Molecular; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Phosphatidylinositol Phosphates; Phosphorylation; Phosphoserine; Protein Binding; Protein Kinase C-alpha; Protein Structure, Tertiary; Proteoglycans; Rats; Signal Transduction; Substrate Specificity; Syndecan-4
PY - 2005
Y1 - 2005
N2 - 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 PKCalpha activity in the presence of PtdIns(4,5)P2, emphasizing the importance of multimerization in the regulation of PKCalpha 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 PKCalpha 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.
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 PKCalpha activity in the presence of PtdIns(4,5)P2, emphasizing the importance of multimerization in the regulation of PKCalpha 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 PKCalpha 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.
U2 - 10.1016/j.jmb.2005.09.087
DO - 10.1016/j.jmb.2005.09.087
M3 - Journal article
C2 - 16310216
VL - 355
SP - 651
EP - 663
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 4
ER -
ID: 5160853