Conformational Ensembles from Experimental Data and Computer Simulations

74 / 161

Conformational Ensembles from Experimental Data
and Computer Simulations Poster Abstracts
70
37-POS Board 37
Functional Role of the TCTP Intrinsically Disordered Region Investigated by MD
Simulations and NMR Experiments
Florian Malard1, Nadine Assrir1, Ewen Lescop 1, Mouad Alami2, Samir Messaoudi2 , Tâp Ha-
Duong2.
1CNRS, Gif-sur-Yvette, France, 2Université Paris-Sud, Châtenay-Malabry, France.
The translationally controlled tumor protein (TCTP) is involved in several biological processes.
To exert its various functions, TCTP is brought to interact with many other biomolecules.
Notably, TCTP residues S46 and S64 can be phosphorylated, impacting its binding with other
proteins. Moreover, TCTP can sequestrate calcium to block the calcium-dependent apoptosis
process. However, little information on the quaternary structures of TCTP complexes are
available, impeding the full understanding of the mechanisms by which TCTP performs its
functions.
The protein three-dimensional structure is composed of a core domain and an intrinsically
disordered loop which contains a highly conserved TCTP signature. The objective of this study
is to explore this disordered loop conformational ensemble, using molecular dynamics
simulations in combination with NMR experiments, to gain a better insight into its functional
role.
The TCTP conformational ensemble was studied under four conditions: without or with calcium,
with residue S46 phosphorylated, and with both S46 and S64 phosphorylated. Simulations show
that, in the absence of calcium, the non-phosphorylated and pS46 protein have overall similar
conformational ensemble. The double phosphorylated pS46-pS64 protein is more extended,
whereas calcium induce a more compact structure. However, in all conditions, the disordered
loop has a similar extent, but is more or less bound to the core domain, hiding accessible surface
area from TCTP partners. Simulations also permit to identify calcium binding sites on TCTP
which were partially confirmed by NMR experiments.
In conclusion, the TCTP intrinsically disordered loop might play the role of a switch which could
interfere with the binding of its multiple partners. Its conformational states depend on the
presence of calcium and on the phosphorylation of residues S46 and S64.