The branchpoint binding protein: In and out of the spliceosome cycle

The Saccharomyces cerevisiae branchpoint binding protein (BBP) is a 53 kDa pre-mRNA processing factor with characteristic STARJ/GSG protein organization. This includes a central RNA binding site composed of an extended Type I KH domain with an adjacent QUA2 motif. Downstream of KH-QUA2 are two CCHC-type zinc knuckles and a proline-rich C-terminal interaction domain (Fig. 1A). The QUA1 homodimerization motif found upstream of the KH-QUA2 sequence in other STAPJGSG family members is absent in BBP and replaced by a site for the phylogenetically conserved binding partner, Mud2/U2AF65. BBP's name reflects the fact that it binds the conserved RNA sequence, UACUAAC, called the branchpoint motif found near the 3' end of yeast introns. This sequence contains the catalytic adenosine (underlined) which directs the first RNA transesterification reaction in splicing chemistry. BBP recruitment to the branchpoint initiates a series of spliceosomal subunit addition and rearrangement events that ultimately configures the active site of this enzyme. ¹The mammalian homolog, ZFM1/ZNF162/D11S636/SF1 (henceforth, SF1), was first identified in a screen for genes associated with Type 1 multiple endocrine neoplasia2 and was subsequently shown to act similarly to BBP in mammalian splicing. ^3,4BBP/SF1 is essential for viability in organisms spanning the evolutionary spectrum from yeast to Caenorhabditis elegans to mice. In addition, mice heterozygous for a SF1 knockout allele show enhanced susceptibility to azoxymethane-induced colon tumorigenesis⁵ adding BBP/SF1 to the growing list of RNA processing factors implicated in genetic disease. ⁶Summarized below is our current understanding of BBP structure and its proposed multifaceted contribution to mRNA biogenesis and function. Reference to SF1 will be made to fill gaps in our understanding of BBP and to highlight areas of clear similarity or difference between yeast and mammals.