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Biography of Erin K. O'shea Biography of Erin K. O’Shea aving little background in biology has not hindered Erin K. O’Shea, professor of H biochemistry and biophysics at the University of California at San Francisco (UCSF) and assistant investi- gator of the Howard Hughes Medical Institute. Trained primarily as a biophys- ical chemist, O’Shea has made her mark in several disciplines. As a graduate stu- dent, she made a significant contribu- tion in her delineation of the physical structure of the leucine zipper motif (1, 2). Her later foray into yeast biology has yielded dozens of publications on signal transduction and proteomics and has established her as a leader in the field of cell and molecular biology. For her many contributions to the fields of biochemistry, biophysics, and cell and molecular biology, O’Shea received the National Academy of Sci- ences (NAS) Award in Molecular Biol- ogy in 2001. Despite earning numerous awards throughout her career, O’Shea notes that the NAS award was the ‘‘big- gest deal’’ for her, because her graduate Erin K. O’Shea. Photograph courtesy of Janet Yang and Brandon Toyama. advisor, Peter Kim [Massachusetts Insti- tute of Technology (MIT), Cambridge, MA], and her postdoctoral advisor, on to solve the crystal structure of a leucine zipper, right after I finished col- Robert Tjian (University of California, leucine zipper two years later (2). With lege,’’ she says. ‘‘I was struggling with Berkeley), had received the award in these discoveries, O’Shea made her whether I should go to medical school, previous years. Also, by O’Shea’s esti- mark on the world of protein structure: and Kim really encouraged me to pur- mates, approximately 25% of winners of ‘‘The reason that this was such a big sue a research career.’’ Kim told O’Shea this award go on to win the Nobel Prize. deal is, first, a lot of proteins have this that she was good enough to succeed in O’Shea was elected to the NAS in coiled-coil region that’s involved in science. ‘‘I’ve never forgotten what he 2004 for her contributions to the under- dimerization—the leucine zipper defines said. In times when things weren’t going standing of signal transduction, regula- a class of transcription factors that are so well, it was something I could think tion of protein movement into and out one of the most common found in mam- about,’’ says O’Shea. ‘‘It’s something of the nucleus, and how phosphorylation malian cells,’’ says O’Shea. The structure that sticks with you.’’ of a coiled coil had been independently controls protein activity. Nucleosomes and Gene Expression proposed by Francis Crick and Linus The Coiled-Coil Leucine Zipper Pauling based on their fiber diffraction O’Shea’s productivity and outstanding After graduating with a bachelor’s de- studies of keratin in the 1950s. O’Shea’s performance during graduate school gree in biochemistry from Smith Col- leucine zipper structure captured their quickly earned her a highly coveted fac- lege (Northampton, MA) in 1988, attention: ‘‘Crick wrote me a letter, con- ulty position offer right out of graduate O’Shea entered Kim’s laboratory at gratulating me on the high-resolution school. Although her faculty position at MIT. A young scientist on the aca- structure,’’ O’Shea notes when recalling UCSF was assured, O’Shea was given demic fast track, O’Shea finished grad- how her paper was received by the pro- some scientific free time. ‘‘They gave me two years to do whatever I wanted to uate school in a mere two and a half tein structure community. do,’’ says O’Shea. She elected to spend years. After reading a paper in Science O’Shea is quick to credit Kim with that time working in the laboratories of (3) that had proposed a structure for putting her on the road to academic Tjian at Berkeley and Ira Herskowitz at the leucine zipper—a region of repeat- success. One of the most important as- UCSF. ing leucine residues—the eager gradu- pects of research lies in asking the right In Tjian’s laboratory, O’Shea began to ate student set out to test it. O’Shea questions and figuring out how to an- think about the focus of her research made synthetic peptides corresponding swer them. According to O’Shea, Kim career. She decided the key question to to the leucine regions of some tran- had ‘‘tremendous intuition for picking address was how gene expression was scription factors, such as the mammalian interesting biological problems. Maybe regulated by chromatin. O’Shea knew factors Fos and Jun and the budding even more important, he really encour- yeast transcription factor Gcn4. She aged me to do science.’’ O’Shea had ␣ showed that they were -helical and intended to get a Ph.D. when joining This is a Biography of a recently elected member of the dimeric but that the orientation of the Kim’s laboratory, but she originally ac- National Academy of Sciences to accompany the member’s helices was not antiparallel, as had been cepted a position in an M.D.͞Ph.D. pro- Inaugural Article on page 14315. proposed, but was parallel (1). She went gram. ‘‘Then I started this work on the © 2004 by The National Academy of Sciences of the USA 14312–14314 ͉ PNAS ͉ October 5, 2004 ͉ vol. 101 ͉ no. 40 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0406675101 Downloaded by guest on October 2, 2021 the topic was not a natural extension of to changes in their extracellular envi- O’Shea notes that teasing out the con- BIOGRAPHY her previous protein structure work. ronment,’’ explains O’Shea. ‘‘I picked a tribution of each phosphorylation ‘‘was ‘‘Tjian took me into his lab at a time model system, this PHO5 promoter. critically important, because this is how when I really didn’t know much biology Then it turns out that PHO5 is one of the cell controls the expression of doz- at all, and that didn’t seem to bother these phosphate-regulated genes, and ens of genes, just by regulating this one him,’’ she says. ‘‘When I decided I that’s how I got to studying the signal- transcription factor. Many transcription wanted to work on chromatin and gene ing part of phosphate regulation.’’ factors and regulatory proteins are mul- expression, I am not sure he thought it Using the budding yeast Saccharomy- tiply phosphorylated, and phosphoryla- was a great idea. But he listened to ces cerevisiae,O’Shea set out to deter- tion is important for their regulation,’’ what I had to say about why I wanted to mine how the cell senses and responds she adds. ‘‘Our studies were really some do it, and he supported me in every way to inorganic phosphate. Previous work of the first to demonstrate mechanisti- possible.’’ by researchers in Japan had already cally how phosphorylation of a protein At that time, much of the transcrip- identified many members of the pathway controls its import into the nucleus and tion field was focused on studying tran- that regulated PHO5 expression (4). export from the nucleus.’’ scription in purified in vitro systems, They had identified PHO2 and PHO4 as with purified components and a piece of Proteomics transcription factors—proteins that bind plasmid DNA, says O’Shea. ‘‘I wanted ‘‘When I was appointed as a Hughes to the PHO5 regulatory region to turn it to take it to the next level and study the investigator four years ago, they chal- DNA template in a more physiological on. Two other pathway members, lenged us to do something new,’’ says context—with nucleosomes assembled,’’ PHO80 and PHO85, seemed to collabo- O’Shea. Together with her graduate she notes. rate to turn off PHO5 expression. school colleague, Jonathan Weissman, O’Shea’s aspirations to study chroma- Despite earlier speculation to the con- O’Shea decided to tackle proteomics. tin and gene expression in a physiologi- trary, O’Shea discovered that PHO80 Their lofty goal: to determine the loca- cal system led her to the laboratory of and PHO85 actually belonged to the tion and the abundance of all 6,200 pro- ͞ Herskowitz, a major figure in the field family of cyclin cyclin-dependent kinase teins encoded by the yeast genome. ͞ of yeast genetics. Herskowitz, who had (cdk) proteins. ‘‘We found a cyclin cdk She and Weissman made two collec- determined the genetic pathways that complex that was involved in a process tions of yeast strains with 6,200 mem- allow budding yeast to change mating other than the cell division cycle; it was bers each—one strain for each gene. CELL BIOLOGY types, offered O’Shea the support she They labeled the genes with GFP and needed to make the jump from beakers analyzed the location of each of the to biology. ‘‘And that’s noise, protein products within the yeast cell ‘‘I had never really worked with living (11). In a similar experiment, they organisms. Really, all I had done was randomness...it’s not tagged each gene with a different label physical chemistry—spectroscopy, pep- to measure the abundance of each tide chemistry, and x-ray crystallogra- predictable.’’ protein (12). Together, O’Shea and phy. I was changing fields,’’ recalls Weissman accomplished an almost in- O’Shea. ‘‘From the beginning, Ira was conceivable goal—they catalogued the so encouraging and never even thought involved the signal transduction pathway location and amount of approximately twice about the fact that I was totally that allows the cells to sense and re- 75% of the proteins encoded by the changing career tracks.’’ spond to inorganic phosphate levels,’’ yeast genome.
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