title: Giant cadherins Fat and Dachsous self-bend to organize properly spaced intercellular junctions.
abstract: The cadherins Fat and Dachsous regulate cell polarity and proliferation via their heterophilic interactions at intercellular junctions. Their ectodomains are unusually large because of repetitive extracellular cadherin (EC) domains, which raises the question of how they fit in regular intercellular spaces. Cadherins typically exhibit a linear topology through the binding of Ca(2+) to the linker between the EC domains. Our electron-microscopic observations of mammalian Fat4 and Dachsous1 ectodomains, however, revealed that, although their N-terminal regions exhibit a linear configuration, the C-terminal regions are kinked with multiple hairpin-like bends. Notably, certain EC-EC linkers in Fat4 and Dachsous1 lost Ca(2+)-binding amino acids. When such non-Ca(2+)-binding linkers were substituted for a normal linker in E-cadherin, the mutant E-cadherins deformed more extensively than the wild-type molecule. To simulate cadherin structures with non-Ca(2+)-binding linkers, we used an elastic network model and confirmed that bent configurations can be generated by deformation of non-Ca(2+)-binding linkers. These findings suggest that Fat and Dachsous self-bend due to the loss of Ca(2+)-binding amino acids from specific EC-EC linkers, and can therefore adapt to confined spaces.
authors.affiliation: RIKEN Center for Developmental Biology, Kobe 650-0047, Japan; RIKEN Center for Quantitative Biology, Suita, Osaka 565-0874, Japan;
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tsukasaki
authors.affiliation: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita, Osaka 565-0871, Japan; and.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Miyazaki
authors.affiliation: Molecular Modeling and Simulation Group, Quantum Beam Science Directorate, Japan Atomic Energy Agency, Kizugawa, Kyoto 619-0215, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
authors.forename: Shigenori
authors.initials: S
authors.lastname: Nagae
authors.affiliation: RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Yonemura
authors.affiliation: RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanoue
authors.affiliation: Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Suita, Osaka 565-0871, Japan; and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: RIKEN Center for Developmental Biology, Kobe 650-0047, Japan; takeichi@cdb.riken.jp.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeichi
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007365:Intercellular Junctions / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; D002118:Calcium; D025521:Tumor Suppressor Proteins; C442479:DCHS1 protein, human; C506554:Dchs1 protein, mouse; C534294:FAT4 protein, human; C506555:Fat4 protein, mouse
keywords: Dachsous; Fat; cadherin superfamily; cell junctions; electron microscope tomography