Structural transitions in TCTP tumor protein upon binding to the anti-apoptotic protein family member Mcl-1.

Abstract

Translationally Controlled Tumor Protein (TCTP) serves as a pro-survival factor in tumor cells, inhibiting the mitochondrial apoptosis pathway by enhancing the function of anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-xL. TCTP specifically binds to Bcl-xL, preventing Bax-dependent Bcl-xL-induced cytochrome c release, and it reduces Mcl-1 turnover by inhibiting its ubiquitination, thereby decreasing Mcl-1-mediated apoptosis. TCTP harbors a BH3-like motif that forms a β-strand buried in the globular domain of the protein. In contrast, the crystal structure of the TCTP BH3-like peptide in complex with the Bcl-2 family member Bcl-xL reveals an α-helical conformation for the BH3-like motif, suggesting significant structural changes upon complex formation. Employing biochemical and biophysical methods, including limited proteolysis, circular dichroism, NMR, and SAXS, we describe the TCTP complex with the Bcl-2 homolog Mcl-1. Our findings demonstrate that full-length TCTP binds to the BH3 binding groove of Mcl-1 via its BH3-like motif, experiencing conformational exchange at the interface on a micro- to milli-second timescale. Concurrently, the TCTP globular domain becomes destabilized, transitioning into a molten-globule state. Furthermore, we establish that the non-canonical residue D16 within the TCTP BH3-like motif reduces stability while enhancing the dynamics of the intermolecular interface. In conclusion, we detail the structural plasticity of TCTP and discuss its implications for partner interactions and future anticancer drug design strategies aimed at targeting TCTP complexes.

• Authors: Florian Malard, Christina Sizun, Aurélien Thureau, Ludovic Carlier, Ewen Lescop
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 299 Issue 7 Pg. 104830 (07 2023) ISSN: 1083-351X [Electronic] United States
• PMID: 37201583 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Tumor Protein, Translationally-Controlled 1

Topics

• Apoptosis (genetics)
• Apoptosis Regulatory Proteins (chemistry, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein (chemistry, metabolism)
• Protein Binding (genetics)
• Tumor Protein, Translationally-Controlled 1
• Humans
• Binding Sites
• Protein Structure, Quaternary
• Models, Molecular