The nuclear pore complex of any given human cell could be described as the world’s busiest shipping port. Between 10 million and 100 million shipments of proteins fundamental to cellular processes pass through its gateway around the clock every day of a person’s life. Considering that there are an estimated 75-100 trillion cells in the human body … well, suffice it to say that’s a lot of traffic.
Biophysicist Yuh Min Chook ’88 studies the mechanisms of protein transport through the nuclear membrane by transporter proteins, or Karyopherin betas (Kap betas), and their traffic patterns, seeking to discover how these ships organize and regulate cellular processes.
In 2006, Chook’s lab discovered a new signal by which Kap betas identify their cargoes. This year, her lab identified the structure of the export-Kap beta that transports the majority of proteins from the nucleus into the cytoplasm, including proteins that are involved in human diseases such as cancer, AIDS, and cardiac hypertrophy.
“Kap betas are critically involved in cellular processes such as gene expression, signal transduction, immune response, oncogenesis and viral propagation,” explains Chook, an associate professor and Eugene McDermott Scholar in the Biomedical Research Department of Pharmacology at the University of Texas (UT) Southwestern Medical Center, Dallas. “These processes require that proteins are transported to the proper destination within the nucleus or the cytoplasm.”
Picking Up Signals
Some 10,000 different proteins regularly enter the human cell nucleus, bound and transported by import-Kap betas through the nuclear pore complex, which acts as a gateway between the nucleus and surrounding cytoplasm. A large fraction of these proteins are also ferried out of the nucleus by export-Kaps.
For example, each import-Kap beta probably recognizes at least 1,000 different proteins, using the nuclear localization signals (NLS) contained within these molecules. “Over time, we expect to discover at least 10 classes of NLS signals, one for each import Kap beta,” Chook says. “Currently, however, we know of only two classes of NLS.”
The first, known as the classical NLS, is a simple, short, positively charged molecule, which was discovered in the early 1980s. In 2006, Chook’s lab discovered the second NLS class, PY-NLS, which is larger and more complex than the classical NLS.
Growing up in Malaysia, Chook was keenly interested in biology. “But in Malaysia at that time, becoming a scientist was not a realistic option,” she says. “If you were a good student who was interested in science, the ‘default’ career was medicine.”
Intending to become a physician, Chook entered Bryn Mawr with a dual major in chemistry and biology. However, her professors at Bryn Mawr and Haverford Colleges encouraged her to pursue her true calling as a research scientist. “At Bryn Mawr, nothing was ‘impossible,'” Chook says.
Chook went on to earn her doctorate in biophysics from Harvard University. Her postdoctoral work included a 1996 Life Sciences Research Foundation Postdoctoral Fellowship at Rockefeller University in the lab of Günter Blobel, who received the 1999 Nobel Prize in Medicine for his discovery that proteins have intrinsic signals that govern their transport and localization in the cell.
It was in Blobel’s lab that Chook solved the structure of Kap beta 2, or transportin, which imports proteins into the nucleus that modify, process, and mature messenger RNA, which transfers genetic information transcribed from DNA to the cell’s ribosomes. Several years later, in her own lab at UT Southwestern Medical Center, Chook’s team identified the common features of all the cargoes that allow them to be recognized by transportin. In turn, that led to their discovery of PY-NLS.
Chook’s long-term goals are to understand and classify traffic patterns in and out of the nucleus, and learn how these patterns contribute to overall cellular organization.
“Our hypothesis is that there are functional programs of nuclear trafficking, in which cargoes of a given Kap beta participate together in common functions,” Chook says. “Through coordinated cargo selection, nuclear trafficking could organize and control these cell functions.”
This year, Chook’s lab identified the structure of CRM1, the export-Kap beta that transports the majority of proteins from the nucleus into the cytoplasm, including proteins involved in cancer, HIV infection, and cardiac hypertrophy. Many of these proteins are tumor suppressors. “However, a lot of these proteins are ‘mislocalized’ in cancers,” Chook says. “If a protein that is supposed to be in the nucleus is improperly transported to the cytoplasm instead, it will be unable to suppress the cancer.”
CRM1 is the only transport protein that is inhibited by a known drug, the antibiotic Leptomycin B. In defining the structure of CRM1, Chook’s research explained how this antibiotic can inhibit CRM1 function. “This implies that there are new opportunities to target different parts of CRM1 for discovery of new drugs that block tumorigenic and other pathological cargoes,” she says.
Chook’s lab is collaborating with industry in these efforts. “I had no idea that my research would go in this direction,” Chook says. “I was trying to understand the basic function of the cell. My main goal is to generate fundamental new knowledge.”
However, given the opportunity to work toward an imminent application, especially for human health, Chook says, “I just can’t turn that down. Wow, it is so direct.”