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Giant cadherins Fat and Dachsous self-bend to organize properly spaced intercellular junctions

Tsukasaki, Yoshikazu*; Miyazaki, Naoyuki*; Matsumoto, Atsushi; Nagae, Shigenori*; Yonemura, Shigenobu*; Tanoue, Takuji*; Iwasaki, Kenji*; Takeichi, Masatoshi*

Fat and Dachsous cadherins regulate cell polarity and proliferation via their heterophilic interactions at intercellular junctions. Their ectodomains are unusually large because of the repetitive EC domains, which raises questions 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, while 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 the elastic network model and confirmed that bent configurations can be generated by deformation of the 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 therefore adapt to confined spaces.



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Category:Multidisciplinary Sciences



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