New Cancer Drug Targets May Arise from Solving Key Protein Structure
Scientists at the University of California, Davis report that they have deciphered the structure of kinesin-5, a critical protein that helps cells to divide. The researchers believe their discovery will assist in attempts to block the uncontrolled cell division that takes place in cancer.
“The structure of kinesin-5 is unexpected, and the implications are big” said Jawdat Al-Bassam, Ph.D., assistant professor of molecular and cellular biology at UC Davis, who led the project. It allows us to target it, for example in various forms of cancer. This fills in a major missing piece, because for the first time we can understand how microtubule filaments can be linked together and slide past each other.”
The Al-Bassam team’s study (“Structural basis for the assembly of the mitotic motor Kinesin-5 into bipolar tetramers”) is published online in eLife.
When a cell divides into two new cells, a mitotic spindle forms. Microtubules of protein fan out from each end of the cell, capture chromosomes, and draw them apart into what will become the two new cells. Precise coordination of this process is crucial for cells to divide properly, and for avoiding birth and developmental defects. Cancer cells divide continuously, so this process repeats itself much more often in cancer cells than in normal cells.
The kinesins are a large family of motor proteins that move items around inside cells, said Jonathan Scholey, Ph.D., professor of molecular and cellular biology at UC Davis and an author on the paper. Generally, they have two motor units at one end that can “walk” along a microtubule, dragging cargo attached to the other end of the protein.
Originally identified as a protein essential for mitosis in fungi, kinesin-5 was first purified about 20 years ago by Dr. Scholey's lab who found that it is unusual because it has motor units at both ends, allowing it to link two microtubules and walk them past each other. “It's now understood to be absolutely essential for mitosis in virtually all eukaryotic cells,” according to Dr. Scholey.
Using electron microscopy and X-ray crystallography, the Al-Bassam group determined the atomic structure of the central rod of kinesin-5. They found that it is made up of four long helices of protein bundled together, two running in each direction.
“We report the atomic structure of the bipolar assembly (BASS) domain that directs four kinesin-5 subunits to form a bipolar minifilament,” wrote the investigators in their journal article. “BASS is a novel 26 nm four-helix bundle consisting of two antiparallel coiled-coils at its center, stabilized by alternating hydrophobic and ionic four-helical interfaces, which, based on mutagenesis experiments, are critical for tetramerization.”
The structure also revealed pockets unique to kinesin-5 that could be exploited as targets for new anticancer drugs. Kinesin-5 has been identified as a target for drugs to treat cancers that involve uncontrolled cell division, such as colorectal cancer, Dr. Al-Bassam explained.