TCTP contains a BH3-like domain, which instead of inhibiting, activates Bcl-xL

Sci Rep. 2016 Jan 27;6:19725. doi: 10.1038/srep19725.

Abstract

Translationally Controlled Tumor Protein (TCTP) is anti-apoptotic, key in development and cancer, however without the typical Bcl2 family members' structure. Here we report that TCTP contains a BH3-like domain and forms heterocomplexes with Bcl-xL. The crystal structure of a Bcl-xL deletion variant-TCTP11-31 complex reveals that TCTP refolds in a helical conformation upon binding the BH3-groove of Bcl-xL, although lacking the h1-subregion interaction. Experiments using in vitro-vivo reconstituted systems and TCTP(+/-) mice indicate that TCTP activates the anti-apoptotic function of Bcl-xL, in contrast to all other BH3-proteins. Replacing the non-conserved h1 of TCTP by that of Bax drastically increases the affinity of this hybrid for Bcl-xL, modifying its biological properties. This work reveals a novel class of BH3-proteins potentiating the anti-apoptotic function of Bcl-xL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Biomarkers, Tumor / chemistry
  • Biomarkers, Tumor / metabolism*
  • Cell Membrane Permeability
  • Mice
  • Models, Molecular
  • Multiprotein Complexes / metabolism
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs*
  • Protein Multimerization
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / chemistry
  • bcl-X Protein / metabolism*

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Biomarkers, Tumor
  • Multiprotein Complexes
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • tumor protein, translationally-controlled 1