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Transient Fcho1/2⋅Eps15/R⋅AP-2 Nanoclusters Prime the AP-2 Clathrin Adaptor for Cargo Binding

DOI: 10.1016/j.devcel.2016.05.003 DOI Help

Authors: Li Ma (Department of Cell Biology, University of Pittsburgh School of Medicine) , Perunthottathu k. Umasankar (Department of Cell Biology, University of Pittsburgh School of Medicine) , Antoni G. Wrobel (University of Cambridge) , Anastasia Lymar , Airlie J. Mccoy (University of Cambridge) , Sachin s. Holkar (Department of Cell Biology, University of Pittsburgh School of Medicine) , Anupma Jha (Department of Cell Biology, University of Pittsburgh School of Medicine) , Tirthadipa Pradhan-sundd (Department of Cell Biology, University of Pittsburgh School of Medicine) , Simon c. Watkins (Department of Cell Biology, University of Pittsburgh School of Medicine) , David J. Owen (University of Cambridge) , Linton m. Traub (Department of Cell Biology, University of Pittsburgh School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Developmental Cell , VOL 37 , PAGES 428 - 443

State: Published (Approved)
Published: June 2016
Diamond Proposal Number(s): 11235

Abstract: 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.

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 20/09/2016 13:35

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