Newly identified enzyme group converts protein into cellular traffic signal

Athens, Ga. – An international research team has identified a new group of enzymes that may help uncover how cells direct internal traffic. The discovery has future implications for conditions – such as polycystic kidney disease, male infertility, behavioral disorders and cancer – that involve defects in protein fibers called microtubules. The findings, which will be prereleased online in Science Express on May 12 will be published in a June issue of the journal Science.

The team was co-led by Jacek Gaertig, associate professor of cellular biology at the University of Georgia, and Bernard Eddé of the National Center for Scientific Research (CNRS) in France.

Cells have an internal highway system made of fibers called microtubules. Specialized motor proteins slide along these fibers, carrying organelles and other materials to the places they need to go. But how do motor proteins know where to take their cargoes?

The researchers identified a new enzyme group that attaches an unusual molecular tag to a component of the cell’s microtubular highway system. The tag is attached to a localized region of a microtubule and may act like a road sign on the interstate, directing motor proteins to take the “proper exit” to the nucleus or the cell membrane.

“We’ve known for more than a decade that strings of glutamic acid an amino acid are sometimes attached to the side of a protein called tubulin,” said Gaertig, one of the senior co-authors on the paper. Tubulin is a component of microtubules. “This modification occurs in all cells but is abundant in neurons in the brain.”

Few other proteins are modified in this way. But investigating what the modification does and how it works has been difficult until now.

The authors have identified a new group of enzymes – called polyglutamylases – that attach glutamic acid chains of varying length and branching patterns.

Because the enzyme complex is active only for a short window during development in mice, it took a “biochemical tour de force” by collaborators in France to purify it.

In Gaertig’s group, doctoral student Krzysztof Rogowski then identified the enzyme complex’s active subunit and postdoctoral associate Dorota Wloga found genes for these enzymes in many organisms including humans. The researchers also showed that these enzymes can modify just a portion of a microtubular highway, an important discovery that suggests the mechanism for directing cell traffic. The lab studied polyglutamylases from the unicellular pond protist Tetrahymena, a model organism that has abundant modified microtubules and shares many of the same properties of internal cell traffic as animal cells.

“Although it has been known for some time that polyglutamylation occurs, the function of these glutamic acid chains on microtubules have, until now, remained completely obscure,” Eve Ida Barak, a program director for the National Science Foundation, said in an e-mail.

This research paves the way for detailed studies of what polyglutamylate modification does and how it works.

The UGA research team was supported by an NSF grant.

For more information on Jacek Gaertig’s research, log on to http://gaertig4.cb.uga.edu.