I remember the first time I saw a movie of chromosomes aligned at metaphase in a dividing cell. I was in seventh grade and my 13-year-old mind was largely focused elsewhere, but those first images of
Hongtao Yu
Credit: Amy Gutierrez/AP, ©HHMI
chromosomes condensing from the blob of the nucleus, neatly lining up, and then suddenly coming apart never went away. More than 30 years later, I met someone on whom mitosis has made a far more lasting impression. It has become his life. ASCB member Hongtao Yu is a structural cell biologist in the Department of Pharmacology at the University of Texas (UT) Southwestern Medical Center and a Howard Hughes Medical Institute (HHMI) investigator completely devoted to unraveling the molecular mechanisms of chromosome segregation.
“I have zero other talents,” Yu jokes. “I grew up in China where natural science was a priority.” This turns out not to be entirely true—when pressed, Yu admits that he is a serious long-distance runner—but Yu and his group at UT Southwestern have put their considerable scientific talents to work using protein structural analysis to dissect the structural features of chromosome proteins that allow for precise regulation by the cysteine protease separase.
For chromatid separation to occur, cohesins, ring-shaped protein complexes that hold chromosomes together, must be cleaved in the right location by separase. The process must be tightly regulated, or the daughter cells will end up with extra or lost chromosomes (aneuploidy). Reporting in a recent paper, Yu and his colleagues were able to describe the structural basis for cohesin recognition by separase.1 The challenge began, Yu says, with finding a suitable separase for structural analysis. “This thing [separase] has been found for more than two decades. It is fairly large and contains many repeat sequences, so it is very hard to express and you need to express it with securin [an inhibitory protein that restricts separase activity to the right time and place], and the resulting complex is inactive and unstable.”
Yu continues, “However, the complex is very well conserved, so we screened many organisms and were able to find a separase in a thermophilic fungus, Chaetomium thermophilum, that we could work with.” Once Yu’s team had purified the separase and determined the structure of its catalytic domain, they learned some surprising things about how separase is regulated. Notably, they found similarities between cohesin and securin, and showed that mutating two key residues of securin allowed it to be cleaved by separase. This shows structurally that securin functions as a competitive inhibitor of separase and may allow the design of new separase peptide inhibitors that could be used in cancer treatment.
Another surprise for Yu was the realization that, “Separase has two domains, an active protease domain and an inactive, or pseudo-protease domain, which people thought was just a structural domain. However, our work shows that this actually forms part of the separase active site.” He adds, “We would now like to go after the whole [separase] molecule, including the non-catalytic domains, where there could be other targeting modules for chromatin and for cohesin recognition. We have all sorts of structural tools at our disposal now and can use these to look at the biology; the techniques are getting easier and the pace has picked up.”
Yu has been picking up his pace since completing his chemistry degree at Beijing University and coming to the United States in 1990 for graduate studies. Joining Stuart Schreiber’s lab at Harvard University, Yu solved the structure of the SH3 Src-homology domain for his thesis in 1995. Structural biology was exciting, but Yu found his interests turning toward cellular problems with a structural dimension. He crossed the Charles River to Marc Kirschner’s lab at the Harvard Medical School. In 1999, he left Boston for Dallas and his own lab at UT Southwestern. “I had worked on protein structure but that was not enough, so I did a postdoc with Marc Kirschner. He didn’t do structural work, so I brought this with me. Now I am combining the structural work from grad school with the cell biology from my postdoc.” He became an HHMI investigator in 2008.
Structural cell biology requires patience, discipline, and mental stamina, so perhaps it’s not a surprise that Yu is a long-distance runner. “I’m not a fast runner but I enjoy it and it keeps me focused.” He says. “I’ve run three marathons and I’m training for a triathlon.”
u has been an ASCB member since 2000. “The meetings are very good networking opportunities and I encourage the people in my lab to attend.” He recalls, “One of my postdocs told me he applied to my lab because he remembered me stopping by his poster and the conversation we had.” Besides an ASCB membership, those wishing to join Hongtao Yu on his mission might want to invest in a good pair of running shoes.
Reference
1Lin Z, Luo X, Yu H (2016). Structural basis of cohesin cleavage by separase. Nature 532, 131–134.
About the Author:
Nicholas is a freelance science writer.
