Biochemistry, Structural Biology
The Rockefeller University
Dr. Chen is also a professor and head of the Laboratory of Membrane Biology and Biophysics at the Rockefeller University.
Jue Chen studies the structure of proteins that use energy to transport solutes—necessary nutrients as well as unwanted toxins—across cell membranes. Determining how such transporters work will aid in understanding the basic mechanisms of active transport.
"The Maltose Transporter" may sound like the title of a Humphrey Bogart movie for scientists, but the protein by that name is actually a marquee molecule in its own right—the object of fierce attention from researchers worldwide.
For seven long years, Jue Chen admits that she was obsessed with the maltose ABC transporter. Her quest to solve the three-dimensional structure of that protein complex drew Chen into one of the trickiest mysteries in protein structure. For 30 years, biochemists and geneticists had stacked up data that gave them an excellent idea of what the maltose ABC transporter should be doing, yet no one had ever produced detailed pictures of the transporter in action. Chen made that her goal.
The maltose ABC transporter ferries sugar molecules, a class of nutrients that support growth, through a cell's membrane to its interior. After one of those sugars, maltose, is transported inside the cell, it is converted into the energy source adenosine triphosphate (ATP). ATP powers the ABC transporter, which then opens and resets its transmembrane gates for the next delivery of maltose.
There are ABC transporters everywhere there are cells—from bacteria to mammals. ABC transporters import or export a bewildering variety of cellular products and extracellular raw materials, including lipids, sugars, and drugs. The average E. coli bacterium, for example, has more than 80 different ABC transporters on board, pumping things in and out of the cell. ABC transporters are also the central engines behind multidrug resistance in many pathogenic bacteria because they help purge toxic compounds, such as antibiotics. In humans, more than a dozen genetic diseases have been traced to ABC-transporter defects, including cystic fibrosis.
Chen is a structural biologist and an expert in x-ray crystallography. Like all structural biologists, she wants to see cells or parts of cells going about their business, resolved in exquisite detail at the atomic and molecular level. Chen crystallizes the proteins she is interested in and then bombards them with x-rays. Computers help capture the diffraction patterns that bounce off the atomic lattice. By rotating the crystallized protein complexes through multiple exposures, Chen gradually builds three-dimensional computer models that expose the architecture of these natural nanomachines.
Chen was born in Changsha in China's Hunan province and studied chemistry at Tongji University in Shanghai. During her senior year at Tongji, she transferred to Ohio University in Athens where her uncle was a professor of mathematics. After graduating from Ohio University, she journeyed to Harvard University and the lab of the late HHMI investigator Don Wiley for graduate and postdoctoral studies in crystallography.
Chen began to study ABC transporters in 1999 as a postdoctoral fellow in the laboratory of Florante Quiocho, who was an HHMI investigator at the Baylor College of Medicine in Houston. At Baylor, Chen also met biochemist Amy Davidson, who introduced her to the maltose ABC-transporter puzzle and suggested possible ways that they might solve it by "trapping" the transporter in its three working positions—resting, transition, and posthydrolysis.
The maltose ABC transporter has five major molecular pieces—a maltose-binding protein in the periplasm that carries the maltose cargo into docking position with two integral membrane proteins, MalF and MalG, which act as the gate. In addition, two copies of MalK, a cytoplasmic ATPase, work together as the engine that powers the pump.
Chen soon discovered that the MalF and MalG membrane proteins are festooned with helices and periplasmic loops that make them difficult to crystallize, but the major stumbling block was trapping the ABC transporter in mid-action. In the middle position, the catalytic transition state, the transporter's engine is held in place by ATP while the membrane gate is open to grab the incoming maltose. Crystallizing the transporter at this fleeting moment seemed impossible. A potential solution appeared in the discovery of an E. coli mutant with an otherwise normal maltose transporter that would lock up at this precise step, theoretically giving Chen and colleagues time to crystallize the machinery.
When Chen left Baylor in 2002 for her first faculty position at Purdue, she set up a new crystallography laboratory. Solving the structure of the maltose transporter became the central goal of her new research group. Scientific mentors suggested that it might be too narrow a project. One adviser warned that as a junior researcher, Chen could be "betting the farm" on a problem that was beyond current technology.
Chen listened to their advice, but stayed the course. Working with Davidson, who had also come to Purdue in 2005, Chen improved her crystals and refined her diffraction analysis. Gradually, Chen revealed key parts of the ABC-transporter apparatus, including a breakthrough solution of the "engine," the pair of MalK molecules that power it. Then in a 2007 article in Nature, Chen and colleagues published a complete solution of the maltose transporter in its elusive mid-action position.
Looking back, Chen says that it wasn't obstinacy or the chance of having a high-profile publication that motivated her. "I was doing this because I was just so interested in the molecule," she recalls. "I told people that I was obsessed. I just had to see it." Solving the maltose transporter puts Chen's lab on the leading edge of the ABC-transporter field.
Chen says that being named an HHMI investigator will allow her to apply the lessons learned from the maltose transporter project to other biologically significant structures, such as the multidrug resistance proteins that protect cancer cells against a variety of chemotherapy drugs by simply pumping the agents back out before they can take effect. Chen also plans to expand her expertise from x-ray crystallography of three-dimensional crystals to cryo-electron microscopy of two-dimensional crystals. In the future, she hopes to combine both techniques to determine the structure of membrane transporters.
In July 2014 Chen moved from Purdue to the Rockefeller University.