Structural recognition mechanisms between human Src homology domain 3 (SH3) and ALG-2-interacting protein X (Alix)

Xiaoli Shi, Stephane Betzi, Adrien Lugari, Sandrine Opi, Audrey Restouin, Isabelle Parrot, Jean Martinez, Pascale Zimmermann, Patrick Lecine, Mingdong Huang, Stefan Arold*, Yves Collette, Xavier Morelli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The functions of Src family kinases are tightly regulated through Src homology (SH) domain-mediated protein-protein interactions. We previously reported the biophysical characteristics of the apoptosis-linked gene 2-interacting protein X (Alix) in complex with the haemopoietic cell kinase (Hck) SH3 domain. In the current study, we have combined ITC, NMR, SAXS and molecular modeling to determine a 3D model of the complex. We demonstrate that Hck SH3 recognizes an extended linear proline-rich region of Alix. This particular binding mode enables Hck SH3 to sense a specific non-canonical residue situated in the SH3 RT-loop of the kinase. The resulting model helps clarify the mechanistic insights of Alix-Hck interaction. Structured summary of protein interactions: Hck physically interacts with SAM68 by two hybrid (View interaction) FynR96I physically interacts with Alix by two hybrid (View interaction) Hck binds to Alix by pull down (View interaction) Fyn physically interacts with SAM68 by two hybrid (View interaction) Hck and Alix bind by nuclear magnetic resonance (View interaction) FynR96I and Alix bind by isothermal titration calorimetry (View Interaction: 1, 2) FynR96I and Alix bind by nuclear magnetic resonance (View interaction) FynR96I binds to Alix by pull down (View interaction) Hck physically interacts with Alix by two hybrid (View interaction) FynR96I and Alix bind by x ray scattering (View interaction) Hck physically interacts with NEF by two hybrid (View interaction) FynR96I physically interacts with NEF by two hybrid (View interaction).

Original languageEnglish (US)
Pages (from-to)1759-1764
Number of pages6
JournalFEBS Letters
Volume586
Issue number13
DOIs
StatePublished - Jun 21 2012

Keywords

  • Apoptosis-linked gene 2-interacting protein X (Alix)
  • NMR
  • Protein-protein interaction
  • SAXS
  • Src family kinase (SFK)
  • Src homology 3 domain (SH3 domain)

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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