title: A unique phenylalanine in the transmembrane domain strengthens homodimerization of the syndecan-2 transmembrane domain and functionally regulates syndecan-2.
abstract: The syndecans are a type of cell surface adhesion receptor that initiates intracellular signaling events through receptor clustering mediated by their highly conserved transmembrane domains (TMDs). However, the exact function of the syndecan TMD is not yet fully understood. Here, we investigated the specific regulatory role of the syndecan-2 TMD. We found that syndecan-2 mutants in which the TMD had been replaced with that of syndecan-4 were defective in syndecan-2-mediated functions, suggesting that the TMD of syndecan-2 plays one or more specific roles. Interestingly, syndecan-2 has a stronger tendency to form sodium dodecyl sulfate (SDS)-resistant homodimers than syndecan-4. Our structural studies showed that a unique phenylalanine residue (Phe(167)) enables an additional molecular interaction between the TMDs of the syndecan-2 homodimer. The presence of Phe(167) was correlated with a higher tendency toward oligomerization, and its replacement with isoleucine significantly reduced the SDS-resistant dimer formation and cellular functions of syndecan-2 (e.g. cell migration). Conversely, replacement of isoleucine with phenylalanine at this position in the syndecan-4 TMD rescued the defects observed in a mutant syndecan-2 harboring the syndecan-4 TMD. Taken together, these data suggest that Phe(167) in the TMD of syndecan-2 endows the protein with specific functions. Our work offers new insights into the signaling mediated by the TMD of syndecan family members.
authors.affiliation: From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Mi-Jung
authors.initials: MJ
authors.lastname: Kwon
authors.affiliation: From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Youngsil
authors.initials: Y
authors.lastname: Choi
authors.affiliation: the Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea, and.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yun
authors.affiliation: the Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea, and.
authors.forename: Weontae
authors.initials: W
authors.lastname: Lee
authors.affiliation: the College of Medicine, Department of Physiology and Biophysics, Inha University, Incheon 402-751 Korea.
authors.forename: Inn-Oc
authors.initials: IO
authors.lastname: Han
authors.affiliation: From the Department of Life Sciences, Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea, OhES@ewha.ac.kr.
authors.forename: Eok-Soo
authors.initials: ES
authors.lastname: Oh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007532:Isoleucine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010649:Phenylalanine / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry / Q000378:metabolism; D053669:Syndecan-2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D053671:Syndecan-4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D053671:Syndecan-4; D007532:Isoleucine; D053669:Syndecan-2; D012967:Sodium Dodecyl Sulfate; D010649:Phenylalanine
keywords: Membrane Protein; Proteoglycan; Receptor Regulation; Syndecan; Transmembrane Domain