Molecular machine, not assembly line, assembles microtubules

August 19, 2015

When they think about how cells put together the molecules that make life work, biologists have tended to think of assembly lines: Add A to B, tack on C, and so on. But the reality might be more like a molecular version of a 3-D printer, where a single mechanism assembles the molecule in one go.

Take, for example, tubulin. Building from two subunits, alpha and beta tubulin, this protein assembles into microtubules that play a vital role inside cells - giving structure, pushing or pulling other things around, or providing a track on which other molecules can pull themselves along.

Perhaps most crucially, when cells divide, microtubules form the spindle structure that first aligns the chromosomes in the middle of the cell then pulls them apart, so that each new cell gets one chromosome from each pair. This process often goes wrong in cancer cells, resulting in chromosomal instability.

Jawdat Al-Bassam at the UC Davis Department of Molecular and Cellular Biology and colleagues have now taken a close look at the proteins that assemble tubulin, and found that they comprise a single machine, not a stepped pathway as previously thought. The work is published online in the journal eLife.

The basic unit of tubulin is a dimer of alpha- and beta- tubulin. This dimer gives microtubules directionality, which is key to many of their other properties, such as being able to assemble or disassemble from either end, and allowing motor proteins to walk along them in a specific direction. This unique organization of tubulin is preserved among all living plant and animal cells, because it is essential for way in which microtubules assemble, Al-Bassam said.

Assembling alpha-beta tubulin dimers involves six known genes, Al-Bassam said. The conventional model arranged these proteins as an assembly line starting with alpha and beta subunits and ending with the finished alpha-beta dimer.

"What we showed instead is that largest four of these six genes form a machine that functions as a single entity," Al-Bassam said. They also discovered that a newly discovered subunit, a GTP-ase enzyme of a type usually thought to act as a switch, in fact powers the whole machine using chemical energy. The energy maybe required to build stable alpha and beta tubulin assembly.

"We didn't expect it ourselves," Al-Bassam said.

The researchers worked with the tubulin system from yeast, but the human genes are very similar.

They first tried to reconstitute the system by working with one or two genes at a time, but this "assembly line" approach just didn't work. Then they put all six genes into a single piece of DNA, so that they would all be transcribed together - and found that they could reconstitute the "3-D printer" that assemble tubulin dimers.

Even small defects in the genes that assemble tubulin are associated with serious developmental disorders, such as Kenny-Caffey syndrome and Giant Axonal Neuropathy. Cancer cells often show an inability to separate chromosomes properly during cell division, due to problems with microtubules.

Al-Bassam said the results open up new ways of thinking about tubulin, tubulin-related disorders and molecular biology in general. Understanding this system may provide a new strategy to control microtubules, particularly in cells that are dividing out of control such as in certain cancers.

"It turns out there are lots of things we can think about as these kinds of machines," he said. "Most important functions in cells are carried by molecules that work in groups."
-end-


University of California - Davis

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.