Transient Fcho1/2â‹…Eps15/Râ‹…AP-2 Nanoclusters Prime the AP-2 Clathrin Adaptor for Cargo Binding.
Clathrin-coated vesicles form by rapid assembly of discrete coat constituents into a cargo-sorting lattice. How the sequential phases of coat construction are choreographed is unclear, but transient protein-protein interactions mediated by short interaction motifs are pivotal. We show that arrayed Asp-Pro-Phe (DPF) motifs within the early-arriving endocytic pioneers Eps15/R are ... differentially decoded by other endocytic pioneers Fcho1/2 and AP-2. The structure of an Eps15/R⋅Fcho1 μ-homology domain complex reveals a spacing-dependent DPF triad, bound in a mechanistically distinct way from the mode of single DPF binding to AP-2. Using cells lacking FCHO1/2 and with Eps15 sequestered from the plasma membrane, we establish that without these two endocytic pioneers, AP-2 assemblies are fleeting and endocytosis stalls. Thus, distinct DPF-based codes within the unstructured Eps15/R C terminus direct the assembly of temporary Fcho1/2⋅Eps15/R⋅AP-2 ternary complexes to facilitate conformational activation of AP-2 by the Fcho1/2 interdomain linker to promote AP-2 cargo engagement.
Mesh Terms:
Adaptor Protein Complex 2, Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Sequence, Animals, Clathrin, Clathrin-Coated Vesicles, Endocytosis, HeLa Cells, Humans, Membrane Proteins, Models, Biological, Models, Molecular, Protein Binding, Protein Domains, Protein Interaction Maps, Rats, Transfection
Adaptor Protein Complex 2, Adaptor Proteins, Signal Transducing, Amino Acid Motifs, Amino Acid Sequence, Animals, Clathrin, Clathrin-Coated Vesicles, Endocytosis, HeLa Cells, Humans, Membrane Proteins, Models, Biological, Models, Molecular, Protein Binding, Protein Domains, Protein Interaction Maps, Rats, Transfection
Dev. Cell
Date: Dec. 06, 2015
PubMed ID: 27237791
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