BUB1, in turn, promotes efficient chromosome biorientation by localizing the Aurora B kinase to inner centromere regions via phosphorylation of H2A-T120 ( Kawashima et al., 2010 Yamagishi et al., 2010). The pseudokinase BUBR1 ( Suijkerbuijk et al., 2012a) is a component of the mitotic checkpoint complex ( Chao et al., 2012) and additionally binds the PP2A-B56 phosphatase that is required for stabilizing kinetochore–microtubule interactions ( Foley et al., 2011 Suijkerbuijk et al., 2012b Kruse et al., 2013 Xu et al., 2013). KNL1 itself directly contributes to this through its N-terminal microtubule-binding region ( Welburn et al., 2010 Espeut et al., 2012), but also by localizing the paralogues BUB1 and BUBR1 to kinetochores.
This long, largely unstructured protein is a member of the KNL1/MIS12 complex/NDC80 complex (KMN) network that constitutes the microtubule-binding site of kinetochores ( Cheeseman and Desai, 2008). Widespread divergence in the amount and sequence of these modules in KNL1 homologues may represent flexibility in adapting regulation of mitotic processes to altered requirements for chromosome segregation during evolution.Ĭhromosome biorientation as well as SAC activity critically rely on the kinetochore scaffold KNL1/CASC5/AF15q14/Blinkin (hereafter referred to as KNL1 Cheeseman et al., 2006, 2008 Kiyomitsu et al., 2007). A minimal array of generic BUB recruitment modules in KNL1 thus suffices for accurate chromosome segregation. Remarkably, normal KNL1 function is maintained by replacing all modules with a short array of naturally occurring or identical, artificially designed ones. Increasing numbers of modules concomitantly increase kinetochore BUB1 levels and progressively enhance efficiency of chromosome biorientation. Engineered KNL1 variants with few modules recruit low levels of BUB1 to kinetochores but support a robust checkpoint. We show that KNL1 contains an extensive array of short linear sequence modules that encompass TxxΩ and MELT motifs and that can independently localize BUB1. Central to this is the kinetochore scaffold KNL1 that integrates the functions of various mitotic regulators including BUB1 and BUBR1. Fidelity of chromosome segregation relies on coordination of chromosome biorientation and the spindle checkpoint.
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