New structural insight of C-terminal region of Syntenin-1, enhancing the molecular dimerization and inhibitory function related on Syndecan-4 signaling.
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.
Department of Life Sciences, Division of Life and Pharmaceutical Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
Youngsil
Y
Choi
Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea.
Ji-Hye
JH
Yun
Department of Biology, College of Life Science &Biotechnology, Yonsei University, Seoul 136-791, Republic of Korea.
Jiho
J
Yoo
Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea.
Inhwan
I
Lee
Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea.
Heeyoun
H
Kim
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
Hye-Nam
HN
Son
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
In-San
IS
Kim
Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, Singapore.|Department of Genetic Engineering, College of Life Sciences, Kyung Hee University,Yongin-si Gyeonggi-do, 446-701, Republic of Korea.
Ho Sup
HS
Yoon
Laboratory for Glycobiology, University of Leuven &Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Pascale
P
Zimmermann
Department of Biomedical Sciences, University of Copenhagen, Biocenter, 2200 Copenhagen, Denmark.
John R
JR
Couchman
Department of Biology, College of Life Science &Biotechnology, Yonsei University, Seoul 136-791, Republic of Korea.
Hyun-Soo
HS
Cho
Department of Life Sciences, Division of Life and Pharmaceutical Sciences and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
Eok-Soo
ES
Oh
Department of Biochemistry, College of Life Science &Biotechnology, Yonsei University, Seoul 120-749, Korea.
Weontae
W
Lee
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D018360:Crystallography, X-Ray; D006801:Humans; D008207:Lymphatic Metastasis; D008546:Melanoma, Experimental / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D051381:Rats; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D053671:Syndecan-4 / Q000737:chemistry* / Q000502:physiology; D053676:Syntenins / Q000737:chemistry* / Q000502:physiology
C508307:Sdc4 protein, rat; C492863:Sdcbp protein, rat; D053671:Syndecan-4; D053676:Syntenins