Cbl promotes clustering of endocytic adaptor proteins

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In vivo and in vitro Studies of Adaptor-clathrin Interaction
17:14

In vivo and in vitro Studies of Adaptor-clathrin Interaction

Published on: January 26, 2011

Daniela Jozic1, Nayra Cárdenes, Yonathan Lissanu Deribe

  • 1Division of Protein Structure, National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.

Nature Structural & Molecular Biology
|October 18, 2005
PubMed

Insights

Ubiquitin ligases c-Cbl and Cbl-b control receptor levels by targeting them for degradation. New structures reveal how CIN85 and PIX proteins bind Cbl, explaining EGFR downregulation.

Area of Science:

  • Molecular biology
  • Cell biology
  • Structural biology

Background:

  • c-Cbl and Cbl-b are ubiquitin ligases essential for receptor downregulation.
  • They mediate receptor ubiquitination and lysosomal degradation.
  • Interactions with CIN85 and PIX modulate Cbl function in receptor endocytosis.

Purpose of the Study:

  • To elucidate the structural basis of Cbl interaction with CIN85 and PIX.
  • To understand the mechanism of Cbl-mediated receptor downregulation.

Main Methods:

  • X-ray crystallography to determine the structures of SH3 domains of CIN85 and beta-PIX in complex with a Cbl-b peptide.
  • Solution-based biophysical techniques to study complex formation.
  • In vivo studies to assess the role of ternary complexes in EGFR downregulation.

Main Results:

  • The structures revealed heterotrimeric complexes formed by two SH3 domains and one peptide.
  • Peptide-induced trimerization was observed in solution and facilitated by the peptide sequence.
  • Ternary complexes of CIN85 and Cbl were confirmed in vivo and shown to be critical for EGFR downregulation.

Conclusions:

  • The findings provide a molecular explanation for how Cbl proteins control receptor downregulation.
  • The study highlights a novel mechanism involving heterotrimeric complex formation for regulating receptor endocytosis.

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