Structural transitions in TCTP tumor protein upon Mcl-1 binding - Archive ouverte HAL Access content directly
Preprints, Working Papers, ... Year :

Structural transitions in TCTP tumor protein upon Mcl-1 binding

(1) , (1) , (2) , (3) , (1)
Ludovic Carlier
Ewen Lescop


Translationally Controlled Tumour Protein (TCTP) is a pro-survival factor in tumor cells. TCTP inhibits the mitochondrial apoptosis pathway by potentiating the anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-xL. Specifically, TCTP binds Bcl-xL and inhibits the Bax-dependent Bcl-xL-induced cytochrome c release and TCTP reduces Mcl-1 turnover by inhibiting its ubiquitinylation, thus resulting in decreased Mcl-1 mediated apoptosis. TCTP owns a BH3-like motif forming a β-strand buried in the globular domain of the protein. The crystal structure of TCTP BH3-like peptide in complex with Bcl-xL highlighted the α-helical conformation of TCTP BH3-like motif, suggesting major changes in TCTP structure upon complex formation. However, the structural impact of the interaction on the full-length TCTP and the structural description of TCTP/Mcl-1 interaction are still lacking. Here using biophysical/biochemical methods (NMR, SAXS, circular dichroism, limited proteolysis), we provide an in-depth description of the TCTP/Mcl-1 complex. We demonstrate that full length TCTP binds to the BH3 binding groove of Mcl-1 via its BH3-like motif which interconverts between different binding modes at the micro- to milli-second timescale. As a consequence of the engagement of the BH3-like motif in the interface, the TCTP globular domain is destabilized into a molten-globule state. We also establish that the residue D16 in TCTP BH3-like motif is crucial for the stability and dynamics of the intermolecular interface. As a conclusion, we reveal here in details the structural plasticity of TCTP and discuss its implications for TCTP biology and for future anticancer drug design strategies aiming at targeting TCTP complexes.
Fichier principal
Vignette du fichier
2022.11.05.515280v1.full.pdf (27.89 Mo) Télécharger le fichier
Origin : Files produced by the author(s)

Dates and versions

hal-03864191 , version 1 (21-11-2022)



Florian Malard, Christina Sizun, Aurélien Thureau, Ludovic Carlier, Ewen Lescop. Structural transitions in TCTP tumor protein upon Mcl-1 binding. 2022. ⟨hal-03864191⟩
0 View
0 Download



Gmail Facebook Twitter LinkedIn More