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252 a.a.
116 a.a.
Key reference
DOI no: 10.1074/jbc.M809250200 J Biol Chem 284:13244-13255 (2009) PubMed id: 19276069
Structural Basis for the Antiproliferative Activity of the Tob-hCaf1 Complex. M.Horiuchi, K.Takeuchi, N.Noda, N.Muroya, T.Suzuki, T.Nakamura, J.Kawamura-Tsuzuku, K.Takahasi, T.Yamamoto, F.Inagaki. ABSTRACT
The Tob/BTG family is a group of antiproliferative proteins containing two highly homologous regions, Box A and Box B. These proteins all associate with CCR4-associated factor 1 (Caf1), which belongs to the ribonuclease D (RNase D) family of deadenylases and is a component of the CCR4-Not deadenylase complex. Here we determined the crystal structure of the complex of the N-terminal region of Tob and human Caf1 (hCaf1). Tob exhibited a novel fold, whereas hCaf1 most closely resembled the catalytic domain of yeast Pop2 and human poly(A)-specific ribonuclease. Interestingly, the association of hCaf1 was mediated by both Box A and Box B of Tob. Cell growth assays using both wild-type and mutant proteins revealed that deadenylase activity of Caf1 is not critical but complex formation is crucial to cell growth inhibition. Caf1 tethers Tob to the CCR4-Not deadenylase complex, and thereby Tob gathers several factors at its C-terminal region, such as poly(A)-binding proteins, to exert antiproliferative activity.
Selected figure(s)
Figure 1.
Structure of the TobN138-hCaf1 complex. A, ribbon diagram of the TobN138-hCaf1 complex labeled with secondary structures. hCaf1 is shown in light yellow and TobN138 in gray. Box A and Box B of Tob are shown in red and blue, respectively. The F[o] - F[c]omit map of the interacting residues of Trp-93t and Lys-203t at 1.0 σ contour level is displayed in the right panel. B, the side chains of the active site residues, enclosed by a circle, are shown as ball-and-stick models. C, the electrostatic surface potential of the hCaf1-TobN138 complex calculated by GROMACS. The view shown is from the same orientation as in B. Figs. 1, 4, and 5 were prepared with PyMOL.Figure 5.
Biologically significant motifs in Tob. A, interaction sites of TobN138 with hCaf1. The residues that mediate the association of TobN138 with hCaf1 are shown as a stick model on the ribbon diagram. Water molecules are indicated by green dots. Box A and Box B regions of TobN138 are colored red and blue, respectively. B, Erk binding sites on Tob. The Arg residues binding to Erk are indicated as a stick model and colored purple. The Lys residues identified as the nuclear localization signal are also indicated as a stick model and colored purple. C, putative nuclear export signal (NES82-92) on Tob. The putative nuclear export signal, LX[(1-3)]LX[(2-3)]LXL, is indicated in yellow. The side chains of NES82-92 are shown as a stick model.The above figures are reprinted by permission from the ASBMB: J Biol Chem (2009, 284, 13244-13255) copyright 2009. Figures were selected by the author.
Literature references that cite this PDB file's key reference
PubMed id Reference
19746446 G.S.Winkler (2010).
The mammalian anti-proliferative BTG/Tob protein family.J Cell Physiol, 222, 66-72. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.
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