Conformational Ensemble and Biological Role of the TCTP Intrinsically Disordered Region: Influence of Calcium and Phosphorylation. Issue 11 (25th May 2018)

• Record Type: Journal Article
• Authors: Malard, Florian; Assrir, Nadine; Alami, Mouad; Messaoudi, Samir; Lescop, Ewen; Ha-Duong, Tâp
• Is Part Of: Journal of molecular biology. Volume 430:Issue 11(2018)
• Page Start: 1621
• Page End: 1639
• Publication Date: 2018-05-25
• Subjects: nuclear magnetic resonance -- molecular dynamics -- intrinsically disordered protein -- TCTP–calcium interaction -- TCTP dimerization; TCTP translationally controlled tumor protein -- SSP secondary structure propensity -- NOE nuclear Overhauser effect -- MD molecular dynamics; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2018.04.024
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: The translationally controlled tumor protein (TCTP) is a multifunctional protein that may interact with many other biomolecules, including itself. The experimental determinations of TCTP structure revealed a folded core domain and an intrinsically disordered region, which includes the first highly conserved TCTP signature, but whose role in the protein functions remains to be elucidated. In this work, we combined NMR experiments and MD simulations to characterize the conformational ensemble of the TCTP intrinsically disordered loop, in the presence or not of calcium ions and with or without the phosphorylation of Ser46 and Ser64. Our results show that these changes in the TCTP electrostatic conditions induce significant shifts of its conformational ensemble toward structures more or less extended in which the disordered loop is pulled away or folded against the core domain. Particularly, these conditions impact the transient contacts between the two highly conserved signatures of the protein. Moreover, both experimental and theoretical data show that the interface of the non-covalent TCTP dimerization involves its second signature which suggests that this region might be involved in protein–protein interaction. We also show that calcium hampers the formation of TCTP dimers, likely by favoring the competitive binding of the disordered loop to the dimerization interface. All together, we propose that the TCTP intrinsically disordered region is involved in remodeling the core domain surface to modulate its accessibility to its partners in response to a variety of cellular conditions. Graphical abstract: Unlabelled Image Highlights: The role of the TCTP intrinsically disordered region was poorly studied although it contains a highly conserved amino acid segment. NMR experiments and MD simulations show that the disordered loop transiently binds to the TCTP second signature region. The presence of calcium or phosphorylation of the disordered loop impacts the transient contacts between the two conserved signatures. TCTP was shown to form concentration-dependent non-covalent dimers. The interface of dimerization involves its second signature. The intrinsically disordered region might modulate the TCTP protein–protein interactions in response to various cellular conditions.