Lin

Boudker

Cornell faculty members Hening Lin and Olga Boudker have been named 2015 Howard Hughes Medical Institute (HHMI) investigators, the institute announced May 19.

Lin, professor of chemistry and chemical biology in the College of Arts and Sciences, and Boudker, associate professor of physiology and biophysics at Weill Cornell Medical College, are among the nation’s top biomedical researchers named HHMI investigators this year, with their appointments to begin in September. Lin and Boudker were among 26 investigators chosen from an initial applicant pool of 894.

Lin studies the biochemical function of proteins, and seeks to understand regulatory roles of protein modifications by studying enzymes that regulate those modifications.

One such class of enzymes, called sirtuins, are supposed to catalyze the removal of acetyl groups from proteins, and Lin became interested in the fact that only three of the seven known human sirtuins actually remove acetyl groups efficiently.

By studying one of these “weaker sirtuins,” Sirt5, Lin discovered that the enzyme is better suited to work with malonyl and succinyl groups, which are bulkier than acetyl groups. He has demonstrated that this is a natural function of the enzyme inside cells. His work has suggested that the addition and removal of malonyl and succinyl groups – previously unrecognized forms of protein modification – are likely to be important in regulating protein function.

Lin also discovered that another such weaker siturin, Sirt6, removes a different chemical tag from proteins, and he has shown that this activity promotes cells’ secretion

of tumor necrosis factor, a signaling molecule involved in inflammation. While continuing to study sirtuins, Lin is also investigating other enzymes with unknown functions. Each one, he says, is an opportunity to understand more about physiology and disease.

Boudker’s research interest is in the role of glutamate transporter molecules in neural functioning.

As soon as a neuron in the brain communicates with a neighboring neuron by releasing a burst of the neurotransmitter glutamate, those molecules must be cleared away rapidly to shut off the signal and ready cells for the next communication. Glutamate transporters handle this task, bringing the neurotransmitter back inside cells so that there can be a million times more glutamate inside the cell than outside. Boudker is trying to reveal exactly how this happens.

Studying a closely related transporter from bacteria, Boudker has demonstrated the detailed structure of the protein in its inward-facing state, in which its glutamate-binding region would be exposed to the interior of a cell. Boudker studied the structure, compared it to the protein's outward-facing state, and proposed that the glutamate transporter operates like an elevator, with a large portion of the protein gliding back and forth inside a membrane-embedded scaffold as it shuttles its cargo.

The model deviated from how other transporters were known to function. But within a few years, real-time single-molecule imaging spearheaded by Boudker's lab had confirmed that model. Boudker's ongoing work investigating the glutamate transporter and related molecules could steer drug developers toward new strategies for treating diseases.

HHMI scientists are mid-career researchers with five to 15 years of experience as faculty members. They receive a full salary, benefits, a research budget and money for research space, equipment and other needs. The institute encourages its investigators to push their research fields into new areas of inquiry.

By employing scientists as HHMI investigators, rather than just providing research grants, the institute is guided by the principle of “people, not projects,”

according to the announcement. HHMI investigators have the freedom to explore and, if necessary, to change direction in their research.