Structure of TCTP reveals unexpected relationship with guanine nucleotide-free chaperones

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Abstract

The translationally controlled tumor-associated proteins (TCTPs) are a highly conserved and abundantly expressed family of eukaryotic proteins that are implicated in both cell growth and the human acute allergic response but whose intracellular biochemical function has remained elusive. We report here the solution structure of the TCTP from Schizosaccharomyces pombe, which, on the basis of sequence homology, defines the fold of the entire family. We show that TCTPs form a structural superfamily with the Mss4/Dss4 family of proteins, which bind to the GDP/GTP free form of Rab proteins (members of the Ras superfamily) and have been termed guanine nucleotide-free chaperones (GFCs). Mss4 also acts as a relatively inefficient guanine nucleotide exchange factor (GEF). We further show that the Rab protein binding site on Mss4 coincides with the region of highest sequence conservation in the TCTP family. This is the first link to any other family of proteins that has been established for the TCTP family and suggests the presence of a GFC/GEF at extremely high abundance in eukaryotic cells.

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Figure 1: Sequence alignment of the TCTP family and structure-based alignment with Mss4 and Dss4.
Figure 2: The three dimensional structure and topology of p23fyp.
Figure 3: Fold of p23fyp and comparison with Mss4.
Figure 4: Stereo view of the Sec4 binding site of Mss4 and its counterpart in p23fyp.

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Acknowledgements

We acknowledge the use of the BBSRC U.K. National 800 MHz NMR facility at the University of Cambridge. We thank L. Higgins and S. Sedelnikova, respectively, for expressing and purifying protein samples; D. Nietlispach for expert assistance at the 800 MHz facility; P. Simpson and P. Artymiuk for many helpful discussions and a referee for bringing the recent publication of Zhu et al. to our attention. This work was supported by project grants and equipment funding from the Wellcome Trust, the British Heart Foundation and the BBSRC. We acknowledge the provision of FELIX software from Molecular Simulations Inc. The Krebs Institute is a designated BBSRC center and a member of NESBIC. J.P.W. is a fellow of the Lister Institute for Preventive Medicine.

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Correspondence to Jonathan P. Waltho or C. Jeremy Craven.

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Thaw, P., Baxter, N., Hounslow, A. et al. Structure of TCTP reveals unexpected relationship with guanine nucleotide-free chaperones. Nat Struct Mol Biol 8, 701–704 (2001) doi:10.1038/90415

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