Biology Department, University of Kentucky, 675 Rose Street, Lexington, Kentucky 40506-0225, USA.
Adv Exp Med Biol. 2010;693:123-41.
The Saccharomyces cerevisiae branchpoint binding protein (BBP) is a 53 kDa pre-mRNA processing factor with characteristic STAR/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 STAR/GSG 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 ofthis enzyme. The 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. BBP/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 tumorigenesis adding BBP/SF1 to the growing list of RNA processing factors implicated in genetic disease. Summarized 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.
酿酒酵母分支点结合蛋白（BBP）是一种 53kDa 的前体 mRNA 加工因子，具有特征性的 STAR/GSG 蛋白结构。它包含一个中央 RNA 结合位点，由伸展的 I 型 KH 结构域和相邻的 QUA2 基序组成。在 KH-QUA2 下游是两个 CCHC 型锌指和一个富含脯氨酸的 C 端相互作用域（图 1A）。在其他 STAR/GSG 家族成员的 KH-QUA2 序列上游发现的 QUAl 同源二聚化基序在 BBP 中缺失，被一个用于系统发育保守结合伴侣 Mud2/U2AF65 的位点取代。BBP 的名称反映了它结合保守 RNA 序列 UACUAAC 的事实，该序列称为在酵母内含子 3' 末端附近发现的分支点序列。这个序列包含催化腺苷（下划线），它指导剪接化学中第一个 RNA 转酯反应。BBP 募集到分支点启动一系列剪接体亚基的添加和重排事件，最终构建该酶的活性位点。哺乳动物同源物 ZFM1/ZNF162/D11S636/SF1（以下简称 SF1）最初在筛选与 1 型多发性内分泌肿瘤相关的基因时被发现，并随后在哺乳动物剪接中被证明与 BBP 具有相似的作用。从酵母到秀丽隐杆线虫再到小鼠，跨越整个进化范围的生物体都需要 BBP/SF1 才能存活。此外，SF1 敲除杂合子小鼠对氧化偶氮甲烷诱导的结肠癌发生的易感性增加，这使得 BBP/SF1 加入到越来越多与遗传疾病相关的 RNA 加工因子之列。下面总结了我们目前对 BBP 结构及其对 mRNA 生物发生和功能的多方面贡献的理解。为了填补我们对 BBP 理解上的空白，并突出酵母和哺乳动物之间明显相似或不同的领域，将提到 SF1。
