A Dartmouth College research team led by chemistry professor F. Jon Kull has recently discovered a new function for NOD, a protein essential for chromosome segregation in meiosis cell division. The finding was published earlier this month in Cell.
When chromosomes do not separate correctly in cell division, serious complications and defects can arise as in the case of cancerous cells. The protein NOD, related to motor proteins that drive cellular activities like transport and cell division via ATP hydrolysis, is from the kinesin-10 family, a family commonly found along the arms (main segments) of meiotic chromosomes. Though NOD itself lacks the capacity for movement along microtubules (MTs), it stimulates microtubule polymerization, highlighting its importance in chromosome segregation.
According to the article, the research team sought for “a model for how a nonmotile kinesin tracks MT plus ends and harnesses the force of MT polymerization to drive the movement of chromosome arms.” Found in fruit flies, the NOD protein will help determine how related proteins in humans work.
The researchers revealed an interesting ATPase mechanism of the kinesin-10 NOD, unique among other kinesin motors, through detailed structural, kinetic and thermodynamic methods. Using X-ray crystallography and cryo-electron microscopy (a form of electron microscopy where the sample is studied at very low temperatures), the researchers determined NOD’s structure, revealing an alternate conformation of the microtubule binding region and a nucleotide-sensitive active site.
Further thermodynamic studies and kinetic analysis showed that NOD binds tightly to microtubules only in the nucleotide-free state. Unlike other kinesins, NOD detaches from the microtubule prior to ATP hydrolysis to ADP. With these results, the researchers were able to propose an in vivo model for NOD function.
“This study on NOD provided evidence for a new way a kinesin motor could function. Rather than moving on its own, it hitches a ride on the ends of microtubules, which results in a dynamic cross-linking between the arms of chromosomes and the cell’s growing spindle of microtubules. If NOD doesn’t function properly, then the two cells end up with either both or none of that particular chromosome, which is lethal [to the cell and the organism] in most cases,” said Jared Cochran, a postdoctoral fellow at Dartmouth and the lead author of the study, in the press release.
The research is at the frontier in providing a better understanding of the intricate mechanics of cell division.
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