When cells divide, a spindle-like structure composed of thousands of filaments called microtubules attaches to chromosomes and pulls equal numbers of them into each newly forming cell. Each microtubule is assembled from individual tubulin molecules and, because errors in chromosome segregation can lead to cancer, it is vital that they assemble into microtubules at the right time and place to form a functional spindle apparatus. Branching microtubule nucleation, in which a new microtubule forms from the side of an existing one, is crucial to this process because it allows the cell to form large numbers of microtubules that all point toward chromosomes, enabling their capture by the spindle.
Branching microtubule nucleation depends on several pieces of molecular machinery. One piece, called the gamma-tubulin ring complex (γ-TuRC), initiates the assembly of tubulin molecules into microtubules, while another, known as the augmin complex, recruits γ-TuRC to the side of existing microtubules. A protein called TPX2, whose levels are elevated in over 25% of all cancers, is also involved in branching microtubule nucleation. Elevated TPX2 levels lead to both aberrant microtubule assembly in cells and poor outcomes in cancer patients. But how TPX2 works with augmin and γ-TuRC to mediate branching microtubule nucleation and spindle assembly has remained unknown.
Mechanism - Microtubule - Nucleation - Process - Cell
"To better understand the mechanism of branching microtubule nucleation, we set out to reconstitute the process outside of the cell using purified proteins," said Sabine Petry, assistant professor of molecular biology at Princeton.
In the eLife study, graduate students Raymundo Alfaro-Aco and Akanksha Thawani describe how they recreated branching microtubule nucleation in a test tube. One key finding from the study is that, like augmin, TPX2 can bind to microtubules and recruit γ-TuRC to initiate branching microtubule nucleation. Another surprising finding was that TPX2 also helps recruit augmin to microtubules, further enhancing the recruitment of γ-TuRC.
Branching - Microtubule
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