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The signal recognition particle (SRP) system regulates the process that directs many proteins to their correct destinations in cell membranes. In recognition of their pioneering mechanistic studies on the fidelity of protein targeting mediated by SRP, Shu-ou Shan, a professor of chemistry at California Institute of Technology, and her former Ph.D. student Xin Zhang are being honored.
“At the core of Dr. Zhang’s graduate work was the generation and analysis of conformationally sensitive fluorescent probes that differentiate intermediate states of the SRP to characterize their interconversions and energetics, emphasizing how these conformational dynamics control the targeting reaction,” says Douglas C. Rees. Their research “culminated in a remarkable contribution establishing how the conformational changes in SRP provide a series of checkpoints that govern the overall fidelity of protein localization by the SRP,” according to Rees, who is a professor of chemistry and chemical engineering at Caltech and a Howard Hughes Medical Institute investigator.
The work overturned dogma that substrate selection by the SRP is governed solely by the affinity of the SRP for the cargo protein’s signal sequence, Rees says. Zhang, who is 33, and Shan, who is 38, “have elevated the field to a level of quantitative analysis that represents the forefront of enzymology, thereby connecting cell biology to rigorous mechanistic chemistry for this vital biochemical process,” he adds.
Daniel Herschlag, a professor of biochemistry at Stanford University, says Zhang’s research “is groundbreaking work—a paradigm for the application of chemical principles to understanding, quantitatively and in-depth, the fundamental behavior of complex biological systems.” And Herschlag says Shan also deserves credit: “I emphasize the remarkable training that Dr. Zhang received in the Shan lab. Starting from a background in theoretical chemistry, with no grounding in biology or even experimental research, Dr. Zhang was able to not just succeed but to thrive at the highest level. This accomplishment alone speaks to a combination of high expectations and trust in a new graduate student to flourish in a new area.”
Zhang’s thesis, “Multistate GTPases Control Cotranslational Protein Targeting,” represents a “biochemical tour de force,” says Sandra L. Schmid, a cell biology professor at Scripps Research Institute. Zhang and Shan, she says, “realized they needed quantitative data on the kinetic and thermodynamic parameters of the many sequential stages governed by protein interactions and conformational changes that drive cargo selection, docking, and translocation.” The work required the development and rigorous execution of “incredibly sophisticated and very difficult fluorescence-based assays for each step,” she adds.
Shan received a B.S. in chemistry and biochemistry from the University of Maryland in 1994 and a Ph.D. in biochemistry from Stanford University in 2000 under Herschlag.
Zhang received a B.S. in chemical physics from the University of Science & Technology of China in 2001, an M.S. in chemical physics from Dalian Institute of Chemical Physics in China in 2004, and a Ph.D. in chemistry from Caltech in 2010. He is now a postdoctoral fellow at Scripps.
Zhang and Shan will present the award address before the ACS Division of Biological Chemistry.