Structural basis for the antiproliferative activity of the Tob-hCaf1 complex

Masataka Horiuchi; Kosei Takeuchi; Nobuo Noda; Nobuyuki Muroya; Toru Suzuki; Takahisa Nakamura; Junko Kawamura-Tsuzuku; Kiyohiro Takahasi; Tadashi Yamamoto; Fuyuhiko Inagaki

doi:10.1074/jbc.M809250200

Structural basis for the antiproliferative activity of the Tob-hCaf1 complex

J Biol Chem. 2009 May 8;284(19):13244-55. doi: 10.1074/jbc.M809250200. Epub 2009 Mar 10.

Authors

Masataka Horiuchi¹, Kosei Takeuchi, Nobuo Noda, Nobuyuki Muroya, Toru Suzuki, Takahisa Nakamura, Junko Kawamura-Tsuzuku, Kiyohiro Takahasi, Tadashi Yamamoto, Fuyuhiko Inagaki

Affiliation

¹ Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
COS Cells
Catalytic Domain
Cell Proliferation
Chlorocebus aethiops
Exoribonucleases
Humans
Intracellular Signaling Peptides and Proteins / chemistry*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Kidney / cytology
Kidney / metabolism
Mice
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Molecular Sequence Data
NIH 3T3 Cells
Nuclear Export Signals
Protein Binding
Protein Conformation
Saccharomyces cerevisiae
Sequence Homology, Amino Acid
Transcription Factors / chemistry*
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Proteins / chemistry*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
X-Ray Diffraction

Substances

CNOT8 protein, human
Intracellular Signaling Peptides and Proteins
Nuclear Export Signals
TOB1 protein, human
Transcription Factors
Tumor Suppressor Proteins
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Exoribonucleases
poly(A)-specific ribonuclease