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Eg5 is a kinesin-like motor protein required for mitotic progression in higher eukaryotes. It is thought to cross-link antiparallel microtubules, and provides a force required for the formation of a bipolar spindle. Monastrol causes the catastrophic collapse of the mitotic spindle through the allosteric inhibition of Eg5. Utilizing a truncated Eg5 protein, we employ difference infrared spectroscopy to probe structural changes that occur in the motor protein with monastrol in the presence of either ADP or ATP. Difference FT-IR spectra of Eg5-monastrol-nucleotide complexes demonstrate that there are triggered conformational changes corresponding to an interconversion of secondary structural elements in the motor upon interaction with nucleotides. Notably, conformational changes elicited in the presence of ADP are different from those in the presence of ATP. In Eg5-monastrol complexes, exchange of ADP is associated with a decrease in random structure and an increase in alpha-helical content. In contrast, formation of the Eg5-monastrol-ATP complex is associated with a decrease in alpha-helical content and a concomitant increase in beta-sheet content. One or more carboxylic acid residues in Eg5 undergo unique changes when ATP, but not ADP, interacts with the motor domain in the presence of monastrol. This first direct dissection of inhibitor-protein interactions, using these methods, demonstrates a clear disparity in the structural consequences of monastrol in the presence of ADP versus ATP.
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PMID:Disparity in allosteric interactions of monastrol with Eg5 in the presence of ADP and ATP: a difference FT-IR investigation. 1528 21

Targeting protein for Xklp2 (TPX2) activates the Ser/Thr kinase Aurora A in mitosis and targets it to the mitotic spindle [1, 2]. These effects on Aurora A are mediated by the N-terminal domain of TPX2, whereas a C-terminal fragment has been reported to affect microtubule nucleation [3]. Using the Xenopus system, we identified a novel role of TPX2 during mitosis. Injection of TPX2 or its C terminus (TPX2-CT) into blastomeres of two-cell embryos led to potent cleavage arrest. Despite cleavage arrest, TPX2-injected embryos biochemically undergo multiple rounds of DNA synthesis and mitosis, and arrested blastomeres have abnormal spindles, clustered centrosomes, and an apparent failure of cytokinesis. In Xenopus S3 cells, transfection of TPX2-FL causes spindle collapse, whereas TPX2-CT blocks pole segregation, resulting in apposing spindle poles with no evident displacement of Aurora A. Analysis of TPX2-CT deletion peptides revealed that only constructs able to interact with the class 5 kinesin-like motor protein Eg5 induce the spindle phenotypes. Importantly, injection of Eg5 into TPX2-CT-arrested blastomeres causes resumption of cleavage. These results define a discrete domain within the C terminus of TPX2 that exerts a novel Eg5-dependent function in spindle pole segregation.
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PMID:Spindle pole regulation by a discrete Eg5-interacting domain in TPX2. 1837 77

Mitotic Aurora-A kinase was found to be required for formation of bipolar spindle, ensuring accurate chromosome segregation in mitosis. Recently, Aurora-A was shown to promote Ran-GTP-induced spindle formation and astral microtubule development. Here, by selective immunodepletion, we showed that Aurora-A was required for centrosome- but not Ran-GTP-induced astral microtubule formation in Xenopus egg extracts. Aurora-A enhanced microtubule polymerization in both centrosome- and Ran-GTP-induced aster assemblies: shortening the timing of aster assembly and increasing the aster size. Indeed, adding of Aurora-A protein alone induced microtubule clustering, which was abrogated by Aurora kinase inhibitory small molecule ZM447439. In addition, we showed that Aurora-A was indispensable for Ran-GTP-induced bipolar spindle formation. Inhibition of Aurora-A activity by adding of kinase inactive dominant mutant led to spindle collapse and formation of monopolar spindle whereas minus-end motor protein dynein/dynactin inhibitor p50/dynamitin rescued the bipolar structure. Lastly, we revealed that Aurora-A was necessary for microtubule poleward flux and this requirement depended on kinase activity. Thus, we showed that Aurora-A promoted microtubule polymerization and maintained microtubule flux in ensuring proper bipolar spindle assembly.
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PMID:Requirement of aurora-A kinase in astral microtubule polymerization and spindle microtubule flux. 1841 60

Membrane fusion underlies multiple processes, including exocytosis of hormones and neurotransmitters. Membrane fusion starts with the formation of a narrow fusion pore. Radial expansion of this pore completes the process and allows fast release of secretory compounds, but this step remains poorly understood. Here we show that inhibiting the expression of the small GTPase Cdc42 or preventing its activation with a dominant negative Cdc42 construct in human neuroendocrine cells impaired the release process by compromising fusion pore enlargement. Consequently the mode of vesicle exocytosis was shifted from full-collapse fusion to kiss-and-run. Remarkably, Cdc42-knockdown cells showed reduced membrane tension, and the artificial increase of membrane tension restored fusion pore enlargement. Moreover, inhibiting the motor protein myosin II by blebbistatin decreased membrane tension, as well as fusion pore dilation. We conclude that membrane tension is the driving force for fusion pore dilation and that Cdc42 is a key regulator of this force.
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PMID:Cdc42 controls the dilation of the exocytotic fusion pore by regulating membrane tension. 2514 4

Intracerebral hemorrhage (ICH) is a primary cause of death and disability in adults worldwide. Secondary brain injury (SBI) induced by ICH can lead to impaired mitochondrial function, which ultimately contributes to apoptosis and necrosis. Mitochondrial Rho GTPase 1 (Miro1) is a key regulator of mitochondrial movement and motor protein binding. Although Miro1 has been demonstrated to be implicated in various types of central nervous system damage, its potential effect on ICH-induced SBI has not been studied in detail. Hence, in the present new study, we explored the effect of Miro1 on SBI in vivo and in vitro. Self-body heart blood was injected into the right basal ganglia of the rat brain in vivo. Meanwhile, our in vitro model of ICH was based on the stimulation of oxygen hemoglobin (OxyHb) to neurons. Then, Miro1 was overexpressed both in the brains of rats after ICH in vivo and in OxyHb-treated cultured neurons in vitro. Miro1 overexpression in vivo reduced several pathological indexes such as brain edema, neurobehavioral impairment, and neuronal death. Immunofluorescent staining in vitro showed that overexpression of Miro1 ameliorated neuronal damage via facilitation of mitochondrial transport and distribution. JC-1 staining indicated that overexpression of Miro1 reduced the collapse of mitochondrial membrane potential and enhanced mitochondrial mass. Additionally, live-dead cellular staining and flow cytometry analysis revealed that Miro1 overexpression in cultured neurons reduced both necrotic and apoptotic rates. In contrast, inhibition of Miro1 expression yielded opposite effects to those of Miro1 overexpression. Above all, the upregulation of Miro1 significantly alleviated pathological symptoms on SBI in vivo and in vitro.
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PMID:Miro1 Regulates Neuronal Mitochondrial Transport and Distribution to Alleviate Neuronal Damage in Secondary Brain Injury After Intracerebral Hemorrhage in Rats. 3250 Mar 52