Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography
Abstract E-cadherin adhesion is regulated at the cell surface, a process that can be replicated by activating antibodies. We use cryo-EM and X-ray crystallography to examine functional states of the cadherin adhesive dimer. This dimer is mediated by N-terminal beta strand-swapping involving Trp2, and forms via a different transient X-dimer intermediate. X-dimers are observed in cryo-EM along with monomers and strand-swap dimers, indicating that X-dimers form stable interactions. A novel EC4-mediated dimer was also observed. Activating Fab binding caused no gross structural changes in E- cadherin monomers but can facilitate strand swapping. Moreover, activating Fab binding is incompatible with the formation of the X-dimer. Both cryo-EM and X-ray crystallography reveal a distinctive twisted strand-swap dimer conformation caused by an outward shift in the N-terminal beta strand that may represent a strengthened state. Thus, regulation of adhesion involves changes in cadherin dimer configurations.
Abendroth Jan、Edwards Tom E、Myler Peter J、Hammerson Brad、Bolejack Madison、Maker Allison、Schecterson Leslayann、Gumbiner Barry M、Staker Bart
UCB Pharma||Seattle Structural Genomics Center for Infectious DiseaseUCB Pharma||Seattle Structural Genomics Center for Infectious DiseaseSeattle Structural Genomics Center for Infectious Disease||Center for Global Infectious Disease Research, Seattle Children?ˉs Research Institute||Department of Pediatrics, University of Washington||Department of Biomedical Informatics & Medical Education, University of WashingtonSeattle Structural Genomics Center for Infectious Disease||Center for Global Infectious Disease Research, Seattle Children?ˉs Research InstituteUCB Pharma||Seattle Structural Genomics Center for Infectious DiseaseUniversity of Washington, Department of Biochemistry||Center for Developmental Biology and Regenerative Medicine, Seattle Children?ˉs Research InstituteCenter for Developmental Biology and Regenerative Medicine, Seattle Children?ˉs Research InstituteUniversity of Washington, Department of Biochemistry||Center for Developmental Biology and Regenerative Medicine, Seattle Children?ˉs Research Institute||Department of Pediatrics, University of WashingtonSeattle Structural Genomics Center for Infectious Disease||Center for Global Infectious Disease Research, Seattle Children?ˉs Research Institute
细胞生物学生物物理学分子生物学
Abendroth Jan,Edwards Tom E,Myler Peter J,Hammerson Brad,Bolejack Madison,Maker Allison,Schecterson Leslayann,Gumbiner Barry M,Staker Bart.Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2022.03.21.484361.点此复制
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