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

Xiaoli Shi (1, 2, 3, 4) , Stéphane Betzi (2, 3, 4) , Adrien Lugari (2, 3, 4) , Sandrine Opi (2, 3, 4) , Audrey Restouin (2, 3, 4) , Isabelle Parrot (5) , Jean Martinez (5) , Pascale Zimmermann (2, 3, 4) , Patrick Lecine (6) , Mingdon Huang (1) , Stefan T Arold (7) , Yves Collette (2, 3, 4) , Xavier Morelli (2, 3, 4)

1 State Key Laboratory of Structural Chemistry
2 IPC - Institut Paoli-Calmettes
3 Université de la Méditerranée - Aix-Marseille 2
4 CRCM - Centre de Recherche en Cancérologie de Marseille
5 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
6 INSERM UMR899
7 Department of Biochemistry and Molecular Unit 1000

The functions of Src family kinases are tightly regulated through Src homology (SH) domainmediated 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.

Mots clés: Apoptosis-linked gene 2-interacting protein; X (Alix); Protein-protein interaction; Src homology 3 domain (SH3 domain); Src family kinase (SKF); NMR; SAXS

Domaines: Chimie organique

Xiaoli Shi, Stéphane Betzi, Adrien Lugari, Sandrine Opi, Audrey Restouin, et al.. Structural recognition mechanisms between human Src homology domain 3 (SH3) and ALG-2-interacting protein X (Alix). FEBS Letters, 2012, 586, pp.1759-1764. ⟨10.1016/j.febslet.2012.05.017⟩. ⟨hal-00717171⟩