4.8 Article

Structural basis for the binding of tryptophan-based motifs by δ-COP

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1506186112

关键词

delta-COP mu homology domain-binding motifs; coatomer; COPI; vesicle coat; membrane trafficking

资金

  1. Wellcome Trust [090909, 100140]
  2. Canadian Institute of Health Research
  3. German Research Foundation Clusters of Excellence Inflammation and Interfaces [ECX306]
  4. University of Lubeck
  5. NIH [GM071574]
  6. MRC [U105178845]
  7. Medical Research Council [MC_U105178845] Funding Source: researchfish
  8. MRC [MC_U105178845] Funding Source: UKRI

向作者/读者索取更多资源

Coatomer consists of two subcomplexes: the membrane-targeting, ADP ribosylation factor 1 (Arf1):GTP-binding beta gamma delta zeta-COP F-subcomplex, which is related to the adaptor protein (AP) clathrin adaptors, and the cargo-binding alpha beta'epsilon-COP B-subcomplex. We present the structure of the C-terminal mu-homology domain of the yeast delta-COP subunit in complex with the WxW motif from its binding partner, the endoplasmic reticulum-localized Dsl1 tether. The motif binds at a site distinct from that used by the homologous AP mu subunits to bind Yxx Phi cargo motifs with its two tryptophan residues sitting in compatible pockets. We also show that the Saccharomyces cerevisiae Arf GTPase-activating protein (GAP) homolog Gcs1p uses a related WxxF motif at its extreme C terminus to bind to delta-COP at the same site in the same way. Mutations designed on the basis of the structure in conjunction with isothermal titration calorimetry confirm the mode of binding and show that mammalian delta-COP binds related tryptophan-based motifs such as that from ArfGAP1 in a similar manner. We conclude that delta-COP subunits bind Wx(n(1-6))[WF] motifs within unstructured regions of proteins that influence the lifecycle of COPI-coated vesicles; this conclusion is supported by the observation that, in the context of a sensitizing domain deletion in Dsl1p, mutating the tryptophan-based motif-binding site in yeast causes defects in both growth and carboxypeptidase Y trafficking/processing.

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