癌症高表达蛋白(highly expressed in cancer,Hec1)是一种动粒蛋白,它通过N末端尾巴区与微管间的静电相互作用促进动粒-微管结构的形成。Hec1蛋白与Nuf2p、Spc24p、Spc25p构成Ndc80复合物,Ndc80定位于动粒外板,和其他的动粒蛋白共同作用...癌症高表达蛋白(highly expressed in cancer,Hec1)是一种动粒蛋白,它通过N末端尾巴区与微管间的静电相互作用促进动粒-微管结构的形成。Hec1蛋白与Nuf2p、Spc24p、Spc25p构成Ndc80复合物,Ndc80定位于动粒外板,和其他的动粒蛋白共同作用,参与调节有丝分裂中染色体的正常分离。Hec1蛋白表达量随着细胞周期动态变化,且在分裂旺盛的细胞如肿瘤细胞中高表达。目前Hec1已成为肿瘤基因治疗的靶点,使用不同的病毒载体,如腺病毒载体、腺相关病毒载体、逆转录病毒载体将Hec1的干扰片段导入宫颈瘤或脑胶质瘤细胞后,可引起肿瘤细胞凋亡。展开更多
Error-free mitosis depends on accurate chromosome attachment to spindle microtubules,which is monitored by the spindle assembly checkpoint(SAC)signaling.As an upstream factor of SAC,the precise and dynamic kinetochore...Error-free mitosis depends on accurate chromosome attachment to spindle microtubules,which is monitored by the spindle assembly checkpoint(SAC)signaling.As an upstream factor of SAC,the precise and dynamic kinetochore localization of Mps1 kinase is critical for initiating and silencing SAC signaling.However,the underlying molecular mechanism remains elusive.Here,we demonstrated that the multisite interactions between Mps1 and Ndc80 complex(Ndc80C)govern Mps1 kinetochore targeting.Importantly,we identified direct interaction between Mps1 tetratricopeptide repeat domain and Ndc80C.We further identified that Mps1 C-terminal fragment,which contains the protein kinase domain and C-tail,enhances Mps1 kinetochore localization.Mechanistically,Mps1 C-terminal fragment mediates its dimerization.Perturbation of C-tail attenuates the kinetochore targeting and activity of Mps1,leading to aberrant mitosis due to compromised SAC function.Taken together,our study highlights the importance of Mps1 dimerization and multisite interactions with Ndc80C in enabling responsive SAC signaling.展开更多
文摘癌症高表达蛋白(highly expressed in cancer,Hec1)是一种动粒蛋白,它通过N末端尾巴区与微管间的静电相互作用促进动粒-微管结构的形成。Hec1蛋白与Nuf2p、Spc24p、Spc25p构成Ndc80复合物,Ndc80定位于动粒外板,和其他的动粒蛋白共同作用,参与调节有丝分裂中染色体的正常分离。Hec1蛋白表达量随着细胞周期动态变化,且在分裂旺盛的细胞如肿瘤细胞中高表达。目前Hec1已成为肿瘤基因治疗的靶点,使用不同的病毒载体,如腺病毒载体、腺相关病毒载体、逆转录病毒载体将Hec1的干扰片段导入宫颈瘤或脑胶质瘤细胞后,可引起肿瘤细胞凋亡。
基金supported by the National Key R&D Program of China(2017YFA 0102900 and 2017 YFA 0503600)the National Natural Science Fondation of China(31671407 and 31871359 to Z.D.+4 种基金31621002,31430054,91854203,and 31320103904 to X.Y.31301099 and 21672201 to X.G.31471275 to D.W.),Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19040000)Chinese Academy of Sciences Center for Excellence in Molecular Cell Science(2015 HSC-UE010)MOE Innovative Team(IRT_17R102).
文摘Error-free mitosis depends on accurate chromosome attachment to spindle microtubules,which is monitored by the spindle assembly checkpoint(SAC)signaling.As an upstream factor of SAC,the precise and dynamic kinetochore localization of Mps1 kinase is critical for initiating and silencing SAC signaling.However,the underlying molecular mechanism remains elusive.Here,we demonstrated that the multisite interactions between Mps1 and Ndc80 complex(Ndc80C)govern Mps1 kinetochore targeting.Importantly,we identified direct interaction between Mps1 tetratricopeptide repeat domain and Ndc80C.We further identified that Mps1 C-terminal fragment,which contains the protein kinase domain and C-tail,enhances Mps1 kinetochore localization.Mechanistically,Mps1 C-terminal fragment mediates its dimerization.Perturbation of C-tail attenuates the kinetochore targeting and activity of Mps1,leading to aberrant mitosis due to compromised SAC function.Taken together,our study highlights the importance of Mps1 dimerization and multisite interactions with Ndc80C in enabling responsive SAC signaling.
