Organization of the six human BTG/TOB proteins. The presence of an APRO domain (red) at the N-terminus characterizes the BTG/TOB family. Two more conserved sequences, box A and box B (dark red), constitute signature motifs defining the family. The C-terminal parts of the proteins are less conserved and possess no other known domains except for PAM2 motifs found in the TOB members.

The APRO domain is a conserved adaptor binding the Caf1 deadenylase.
(a) Structure of the CAF1-TOBN138 complex shown as ribbon diagram (PDB entry 2D5R, [12]). CAF1 is shown in gray. For TOBN138, invariant residues are shown in red, well-conserved residues in orange, moderately conserved residues in yellow and non-conserved residues in blue. The degree of conservation is taken from a ClustalW multiple sequence alignment of vertebrate APRO domains (shown in supplemental data). All structural images were prepared using PyMOL (www.pymol.org).
(b) Surface representation of TOBN138 showing the surface in contact with CAF1. The coloring scheme is as in (a).
(c) Surface representation of TOBN138 showing the opposite face as compared to (b). The coloring scheme is as in (a).
(d) The CAF1 regions interacting with TOB1 are conserved only in orthologs from species encoding APRO domains. Clustal W sequence alignments of two regions of CAF1 are shown. Residues found to contact TOBN138 [12] are indicated in black boxes. Note that these residues are not conserved in Arabidopsis and S. pombe, which do not encode APRO-containing proteins in their genomes.

Major mRNA degradation pathways. Deadenylation is the first event observed during most major mRNA decay processes. Deadenylation is biphasic with the first step catalyzed by the PAN2–PAN3 complex (blue–purple); the second step is mediated by CCR4-CAF1 (blue–aqua). After deadenylation, the mRNA is either decapped (yellow) and then rapidly degraded in the 5’ to 3’ direction by Xrn1 (aqua), or alternatively, the body of the mRNA can be degraded in the 3’ to 5’ direction by the exosome (blue). In specific cell types, deadenylated mRNAs can be stored as translationally inactive molecules (not shown).

Models of recruitment of deadenylases onto mRNAs.
(a) a translation-dependent exchange of eRF3 for the PAM2-containing PAN3 (purple) factor on PABP (red) allows the recruitment of the PAN2 deadenylase (blue) and initiation of deadenylation.
(b) Expression of the PAM2-containing TOB1 (pink) recruits the CCR4-CAF1 (aqua–blue) deadenylases onto mRNA possibly bypassing PAN2 and activating deadenylation.
(c) Expression of BTG2 (pink) activates CAF1-dependent deadenylation by an unknown mechanism.