Ning Zheng had a problem. He and a team of colleagues at the University of Washington were trying to determine the structure of one of the most important proteins they had ever studied—a plant cell receptor that is closely related to a family of human proteins involved in many diseases. Much of the structure was apparent, but the receptor had a curious knot of densely packed atoms at its center. "We had no clue what kind of compound it was," Zheng said.
One evening, Zheng was sitting in front of his computer mulling over the problem when his father, a retired biochemist in China, called. "I told him we had this structure we couldn't explain, and he asked me to describe it. He immediately said, 'That must be inositol phosphate.' He turned out to be exactly right." For his inspired insight, Zheng's father was a coauthor of the resulting cover article in a 2007 issue of the journal Nature.
Zheng's work on that protein, the plant receptor TIR1, has been the highlight of an unpredictable career. He studied historical relic conservation as an undergraduate at Fudan University in Shanghai, only to discover when he graduated that "there were no jobs." Convinced by his father that biology can be as mysterious as history, he went to the University of Texas Southwestern Medical Center at Dallas to do graduate work in molecular biophysics, thinking that he would apply some of the chemical techniques he had learned as an undergraduate. There he began doing research in structural biology.
During an HHMI postdoctoral fellowship with HHMI investigator Nikola Pavletich at the Memorial Sloan-Kettering Cancer Center, Zheng was introduced to a family of proteins known as the ubiquitin ligases. "At that time, the importance of the ubiquitin complex hadn't really been recognized," Zheng says. The proteins are part of a system that attaches a molecule called ubiquitin to specific proteins, which marks those molecules for degradation by the cell. The ubiquitin ligases had been seen as "a garbage disposal system," according to Zheng. "Few people cared about how protein gets degraded," he says. "But it turns out that the ubiquitin ligases are vital to the program of cell growth and dispersal. When a cell needs to remove a protein blocking a cellular process, it often uses this system."
The structures Zheng revealed during his postdoctoral fellowship helped show how the ubiquitin ligases act as key regulators of protein activity. If the system fails, the excess proteins that linger in the cell can trigger cancers and neurological disorders. When the system is hijacked by viruses, the host cell will lose its weapons for fighting viral infections.
Zheng continued studying ubiquitin ligases when he came to the University of Washington School of Medicine, but within a few years, his research took another unexpected turn. Work done in a plant biology lab at the University of Indiana caught his attention in 2005, when researchers there discovered that the receptor for the hormone auxin, which regulates plant growth, is, in fact, a ubiquitin ligase. Zheng immediately fired off a note to the lead investigator, Mark Estelle.
"I was writing an e-mail to him, because I had seen his paper, when he sent an e-mail to me asking me if I wanted to get involved," Zheng says. "Five minutes later I told him I did."
Their collaboration has revealed a previously unrecognized regulatory mechanism of protein-protein interaction that could have far-reaching ramifications. Zheng's structural work revealed that TIR1 has an indentation in its surface. Auxin fills the cavity and enables TIR1 to bind with other proteins, whose degradation initiates plant growth. "The auxin acts to glue together two proteins, thereby activating the ubiquitin ligase activity of its receptor," Zheng says.
Human ubiquitin ligases appear to function through protein-protein interactions too. Now Zheng is looking for small molecules that can restore the function of disease-associated defective ubiquitin ligases, which fail to grab their target proteins. Ubiquitin ligases "are believed to be the next-generation drug targets because we now realize that they control so many biological pathways," Zheng says.
As a postdoctoral fellow, Zheng had no idea that plant biology would come to occupy so much of his time. "It was a cancer research center, so not many people talked about plants." But Zheng has excelled as a researcher through his willingness to try new things. "Plants have taught us an important lesson that we're applying in biomedicine."