Oncode Institute, Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nat Cell Biol. 2018 Jul;20(7):800-810. doi: 10.1038/s41556-018-0130-3. Epub 2018 Jun 18.
Faithful chromosome segregation depends on the ability of sister kinetochores to attach to spindle microtubules. The outer layer of kinetochores transiently expands in early mitosis to form a fibrous corona, and compacts following microtubule capture. Here we show that the dynein adaptor Spindly and the RZZ (ROD-Zwilch-ZW10) complex drive kinetochore expansion in a dynein-independent manner. C-terminal farnesylation and MPS1 kinase activity cause conformational changes of Spindly that promote oligomerization of RZZ-Spindly complexes into a filamentous meshwork in cells and in vitro. Concurrent with kinetochore expansion, Spindly potentiates kinetochore compaction by recruiting dynein via three conserved short linear motifs. Expanded kinetochores unable to compact engage in extensive, long-lived lateral microtubule interactions that persist to metaphase, and result in merotelic attachments and chromosome segregation errors in anaphase. Thus, dynamic kinetochore size regulation in mitosis is coordinated by a single, Spindly-based mechanism that promotes initial microtubule capture and subsequent correct maturation of attachments.
姐妹染色单体的正确分离依赖于动粒与纺锤体微管的附着能力。动粒外层在有丝分裂早期短暂扩展形成纤维冠，在捕获微管后致密化。我们发现，动力蛋白衔接蛋白 Spindly 和 RZZ（ROD-Zwilch-ZW10）复合物以动力蛋白非依赖的方式驱动动粒扩展。C 端法尼基化和 MPS1 激酶活性引起 Spindly 的构象变化，促进 RZZ-Spindly 复合物在细胞内和体外形成丝状网状结构的寡聚化。与动粒扩展同时发生的是，Spindly 通过招募动力蛋白，通过三个保守的短线性基序来增强动粒的致密化。无法致密化的扩展动粒与微管发生广泛的、持久的侧向相互作用，这种作用持续到中期，并导致后期的着丝粒连接和染色体分离错误。因此，有丝分裂中动态的动粒大小调节由一个基于 Spindly 的单一机制协调，该机制促进了初始微管捕获和随后附着的正确成熟。
