Protein complex plays catchy number during cell division

CAMBRIDGE, Mass. – Whitehead Institute researchers have identified a protein complex that harnesses energy from protein filaments, called microtubules, to pull chromosomes to opposite ends of a cell during cell division. This protein complex, known as Ska1, is a component of the kinetochore, a larger protein complex that hitches the microtubule ends to the chromosome. 

Although numerous kinetochore proteins have been identified, it was unclear which proteins help facilitate connections to the rapidly shrinking and growing microtubules. The Ska1 complex provides a key missing link between the kinetochore and the microtubules, according to a study published in the March issue of Developmental Cell.

“For me, this missing link was one of the really big, outstanding questions of the kinetochore field,” says Whitehead Member Iain Cheeseman. “During cell division, aligning chromosomes and dragging them to two new cells is almost entirely dependent on the ability to hold onto a dramatically shrinking microtubule. We didn’t know how the kinetochore was holding on.”

Cell division is the process one cell (the mother cell) undergoes to ensure that the two resulting cells have a complete copy of the mother cell’s chromosomes. At the beginning of mitosis, each chromosome is bound to its replicated copy. To divvy up the DNA, the microtubules hook onto the chromosomes’ kinetochores and anchor each chromosome in the pair to opposite ends of the cell.

Tugging on the paired chromosomes, the microtubules line up the chromosomes along the middle of the mother cell. Once properly aligned, the bonds between the paired chromosomes break, and the shortening microtubules pull complete sets of the chromosomes to opposite ends of the mother cell.

A microtubule shortens by peeling back narrow molecular strands from its chromosomal end, creating a large amount of force. In yeast, a protein complex called Dam1 harnesses this force to tow the bulky chromosomes through the highly viscous fluid filling the nucleus. Dam1 forms a sliding ring around the shortening microtubule and is also tethered to the rest of the kinetochore. As strands of the microtubule peel back, the fraying end forces the Dam1 ring to slide toward the microtubule’s opposite end, dragging the kinetochore and its attached chromosome behind.

Although Dam1 has been well studied for several years, researchers had been unable to find a comparable protein in higher organisms, including humans. In this study, the Cheeseman lab notes that a newly identified protein, called Rama1, confers upon the Ska1 complex of human cells some of the same properties Dam1 exhibits in yeast cells, including the ability to move a tiny bead down a peeling microtubule.

“It’s exciting because people have been trying to understand for a long time what couples the energy of a fraying microtubule to make chromosomes move in human cells,” says Julie Welburn, first author of the paper and postdoctoral research in the Cheeseman lab. “This research may be a clue to how that coupling works.”

As of now the Cheeseman lab is uncertain if Ska1 forms a ring, like Dam1, or some other shape around a microtubule. “We haven’t seen a specific shape yet,” says Welburn.  “That’s work for the future.”

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Iain Cheeseman’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also an assistant professor of biology at Massachusetts Institute of Technology.

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Citation

Welburn, J. P., Grishchuk, E. L., Backer, C. B., Wilson-Kubalek, E. M., Yates III, J. R., & Cheeseman, I. M. (2009). The human kinetochore Ska1 complex facilitates microtubule depolymerization-coupled motility. Developmental cell, 16(3), 374-385.