Zaytsev Anatoly V, Ataullakhanov Fazly I, Grishchuk Ekaterina L
Physiology Department, Perelman School of Medicine, University of Pennsylvania, 3700 Hamilton Walk, A401 Richards Building, Philadelphia, PA 19104, USA.
Center for Theoretical Problems of Physicochemical Pharmacology, RAS, Moscow, Russia, 119991 ; Physics Department, Moscow State University, Moscow, Russia, 119899 ; Laboratory of Biophysics, Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia, 117198.
Cell Mol Bioeng. 2013 Dec 13;6(4). doi: 10.1007/s12195-013-0309-4.
Chromosome segregation during mitosis is mediated by spindle microtubules that attach to chromosomal kinetochores with strong yet labile links. The exact molecular composition of the kinetochore-microtubule interface is not known but microtubules are thought to bind to kinetochores the specialized microtubule-binding sites, which contain multiple microtubule-binding proteins. During prometaphase the lifetime of microtubule attachments is short but in metaphase it increases 3-fold, presumably owing to dephosphorylation of the microtubule-binding proteins that increases their affinity. Here, we use mathematical modeling to examine in quantitative and systematic manner the general relationships between the molecular properties of microtubule-binding proteins and the resulting stability of microtubule attachment to the protein-containing kinetochore site. We show that when the protein connections are stochastic, the physiological rate of microtubule turnover is achieved only if these molecular interactions are very transient, each lasting fraction of a second. This "microscopic" time is almost four orders of magnitude shorter than the characteristic time of kinetochore-microtubule attachment. Cooperativity of the microtubule-binding events further increases the disparity of these time scales. Furthermore, for all values of kinetic parameters the microtubule stability is very sensitive to the minor changes in the molecular constants. Such sensitivity of the lifetime of microtubule attachment to the kinetics and cooperativity of molecular interactions at the microtubule-binding site may hinder the accurate regulation of kinetochore-microtubule stability during mitotic progression, and it necessitates detailed experimental examination of the microtubule-binding properties of kinetochore-localized proteins.
有丝分裂过程中的染色体分离由纺锤体微管介导，这些微管通过牢固但不稳定的连接附着在染色体动粒上。动粒 - 微管界面的确切分子组成尚不清楚，但微管被认为与动粒上的特殊微管结合位点结合，这些位点包含多种微管结合蛋白。在前中期，微管附着的寿命较短，但在中期会增加3倍，这可能是由于微管结合蛋白的去磷酸化增加了它们的亲和力。在这里，我们使用数学建模以定量和系统的方式研究微管结合蛋白的分子特性与微管附着于含蛋白动粒位点的稳定性之间的一般关系。我们表明，当蛋白质连接是随机的时，只有当这些分子相互作用非常短暂，每次持续几分之一秒时，才能实现微管周转的生理速率。这个“微观”时间比动粒 - 微管附着的特征时间短近四个数量级。微管结合事件的协同性进一步增加了这些时间尺度的差异。此外，对于所有动力学参数值，微管稳定性对分子常数的微小变化非常敏感。微管附着寿命对微管结合位点处分子相互作用的动力学和协同性的这种敏感性可能会阻碍有丝分裂进程中动粒 - 微管稳定性的精确调节，因此有必要对动粒定位蛋白的微管结合特性进行详细的实验研究。
