Structural basis for the antiproliferative activity of the Tob-hCaf1 complex.
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.
Horiuchi
Masataka
M
Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Takeuchi
Kosei
K
Noda
Nobuo
N
Muroya
Nobuyuki
N
Suzuki
Toru
T
Nakamura
Takahisa
T
Kawamura-Tsuzuku
Junko
J
Takahasi
Kiyohiro
K
Yamamoto
Tadashi
T
Inagaki
Fuyuhiko
F
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D005095:Exoribonucleases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals; D011485:Protein Binding; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014961:X-Ray Diffraction
D005095:Exoribonucleases; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D049790:Nuclear Export Signals; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C489780:CNOT8 protein, human; C098669:TOB1 protein, human