Molecular Cancer Research and Cancer Genomics Centre, Department of Medical Oncology, UMC Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Dev Cell. 2012 Jun 12;22(6):1321-9. doi: 10.1016/j.devcel.2012.03.009.
Chromosomal stability is safeguarded by a mitotic checkpoint, of which BUB1 and Mad3/BUBR1 are core components. These paralogs have similar, but not identical, domain organization. We show that Mad3/BUBR1 and BUB1 paralogous pairs arose by nine independent gene duplications throughout evolution, followed by parallel subfunctionalization in which preservation of the ancestral, amino-terminal KEN box or kinase domain was mutually exclusive. In one exception, vertebrate BUBR1-defined by the KEN box-preserved the kinase domain but allowed nonconserved degeneration of catalytic motifs. Although BUBR1 evolved to a typical pseudokinase in some vertebrates, it retained the catalytic triad in humans. However, we show that putative catalysis by human BUBR1 is dispensable for error-free chromosome segregation. Instead, residues that interact with ATP in conventional kinases are essential for conformational stability in BUBR1. We propose that parallel evolution of BUBR1 orthologs rendered its kinase function dispensable in vertebrates, producing an unusual, triad-containing pseudokinase.
染色体稳定性由有丝分裂检查点来保障，其中 BUB1 和 Mad3/BUBR1 是核心组件。这些同源物具有相似但不完全相同的结构域组织。我们发现 Mad3/BUBR1 和 BUB1 同源物对是在整个进化过程中通过九次独立的基因复制产生的，随后是平行的亚功能化，其中对祖先的、氨基末端 KEN 盒或激酶结构域的保存是相互排斥的。在一个例外中，脊椎动物 BUBR1 由 KEN 盒定义，保留了激酶结构域，但允许催化模体的非保守退化。尽管 BUBR1 在一些脊椎动物中进化为典型的假激酶，但它在人类中保留了激酶结构域。然而，我们发现人类 BUBR1 的假定催化作用对于无错误染色体分离是可有可无的。相反，与传统激酶中的 ATP 相互作用的残基对于 BUBR1 的构象稳定性是必不可少的。我们提出，BUBR1 同源物的平行进化使得其激酶功能在脊椎动物中变得可有可无，产生了一种不寻常的、含有三磷酸腺苷的假激酶。
