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TitleAfadin mediates cadherin-catenin complex clustering on F-actin linked to cooperative binding and filament curvature.
Journal, issue, pagesbioRxiv, Year 2024
Publish dateOct 11, 2024
AuthorsRui Gong / Matthew J Reynolds / Xiaoyu Sun / Gregory M Alushin /
PubMed AbstractThe E-cadherin-β-catenin-αE-catenin (cadherin-catenin) complex couples the cytoskeletons of neighboring cells at adherens junctions (AJs) to mediate force transmission across epithelia. Mechanical ...The E-cadherin-β-catenin-αE-catenin (cadherin-catenin) complex couples the cytoskeletons of neighboring cells at adherens junctions (AJs) to mediate force transmission across epithelia. Mechanical force and auxiliary binding partners converge to stabilize the cadherin-catenin complex's inherently weak binding to actin filaments (F-actin) through unclear mechanisms. Here we show that afadin's coiled-coil (CC) domain and vinculin synergistically enhance the cadherin-catenin complex's F-actin engagement. The cryo-EM structure of an E-cadherin-β-catenin-αE-catenin-vinculin-afadin-CC supra-complex bound to F-actin reveals that afadin-CC bridges adjacent αE-catenin actin-binding domains along the filament, stabilizing flexible αE-catenin segments implicated in mechanical regulation. These cooperative binding contacts promote the formation of supra-complex clusters along F-actin. Additionally, cryo-EM variability analysis links supra-complex binding along individual F-actin strands to nanoscale filament curvature, a deformation mode associated with cytoskeletal forces. Collectively, this work elucidates a mechanistic framework by which vinculin and afadin tune cadherin-catenin complex-cytoskeleton coupling to support AJ function across varying mechanical regimes.
External linksbioRxiv / PubMed:39415991 / PubMed Central
MethodsEM (single particle) / EM (tomography)
Resolution3.1 - 4.7 Å
Structure data

EMDB-47194, PDB-9dva:
F-actin binding interface of alpha-E-catenin ABD (cadherin-catenin complex) and afadin
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-47195: Alpha-E-catenin ABD (cadherin-catenin complex) and afadin bound to bent F-actin
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-47196: Cryo-EM structure of bare F-actin
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-47197: Alpha-E-catenin ABD (cadherin-catenin complex) and afadin bound to straight F-actin
Method: EM (single particle) / Resolution: 4.36 Å

EMDB-47198: Tomogram of the cadherin-catenin-vinculin-afadin complex bound to F-actin
Method: EM (tomography)

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

Source
  • Homo sapiens (human)
  • gallus gallus (chicken)
  • mus musculus (house mouse)
KeywordsSTRUCTURAL PROTEIN / Cytoskeleton / cell adhesion

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