Браслет Cooperblack Imperiali
Barbara Imperiali’s research interests lie at the interface of chemistry and biology. She interrogates biology with a chemical lexicon, using chemically driven strategies to provide new insight into the fundamental processes of life (1). In doing so, she and her team have revealed diverse aspects of protein structure, function, and design, and the role of proteins in cellular function and disease.
Photograph credit: Bachrach Photographers, Boston, MA.
Imperiali, a professor of Biology and Chemistry at the Massachusetts Institute of Technology, says, “I taught organic chemistry to many unwilling students for 25 years,” adding that much of the first semester was spent trying to convince students that chemistry was interesting.
By the second semester, many did indeed catch what she calls “the chemistry bug.” As a result, several generations of chemists and other scientists credit Imperiali for their inspiration. In recognition of her continuing achievements, Imperiali was elected to the National Academy of Sciences in
Early Interest in Science
Imperiali was born on New Year’s Day, She grew up in England, where she attended The Southbank School in Caterham.
“There were four different grades all crammed into one room,” she says. Later, she attended Coloma Grammar School in Croydon. The British grammar school system allows for early specialization in certain subjects and, for Imperiali, there was no question that science was to be her focus. From the age of 14 she dedicated much of her studies to learning about chemistry, physics, biology, and math. She attended University College London, where she earned a Bachelor of Science degree in medicinal chemistry with honors in
The same year, Imperiali made a significant move.
“I shocked everyone at home by coming to the US,” she explains. The primary draw was the Massachusetts Institute of Technology (MIT), where she earned a PhD in synthetic organic chemistry.
Her PhD mentor was organic chemist Satoru Masamune. During her doctoral work Imperiali was involved in the development and application of new techniques for synthesizing the complex and challenging structures of ansamycin antibiotics. Her goal in joining the Masamune group was to become “a molecule maker.” She explains, “I wanted to learn how to build molecules so that I could later use this skill to probe biological systems.
I think that this was a great thing to be able to do because it gave me a special talent in the way that I attacked biological problems.”
Imperiali also spent additional time as a postdoctoral associate in the Masamune laboratory, where she helped to launch a new biochemical project on the enzyme β-ketothiolase.
She gained experience in nearly every aspect of enzyme biology, from extraction and purification to kinetic and structural studies. Additional postdoctoral work at Brandeis University with professor Robert Abeles decisively launched Imperiali's career as a biochemist and chemical biologist.
From toImperiali was at the California Institute of Technology as an assistant professor of chemistry, which later led to a chemistry professorship.
“I have been fortunate to work in some great institutions where inspiration abounds,” she says. Imperiali was at Caltech during the time that chemist Dennis Dougherty was starting to work on applying unnatural amino acid mutagenesis in challenging problems focusing on the functions and interactions of ligand-gated membrane channels and receptors in the Xenopus (frog) oocyte system.
She says, “I think that these studies represent real works of art, and I present them every year when I teach chemical biology.”
Dougherty and others at the time inspired Imperiali to tackle important problems at the chemistry–biology interface.
Return to MIT, Work on Protein Glycosylation
Imperiali returned to MIT inbecoming the Ellen Swallow Richards Professor of Chemistry.
Throughout her career, she has worked on protein glycosylation, which involves the enzyme-catalyzed modification of proteins with complex carbohydrates to alter their structure or function. Glycoproteins are abundant in living organisms, serving important functions related to protein folding and trafficking, immunity, and many other processes.
“One aspect of protein glycosylation that has fascinated me,” she says, “concerns how large glycan structures, which are added during protein translation, affect protein folding, structure, and stability.” With Keith Rickert and Sarah O’Connor, both then graduate students at Caltech, she developed experimental approaches to provide clues on how cotranslational glycosylation might trigger specific conformational changes in the early stages of protein biosynthesis and therefore serve to nucleate future folding events and the ultimate attainment of the protein’s native folded state (2, 3).
Using fluorescence resonance energy transfer and NMR studies, she and her colleagues showed how the glycan structures that are appended to proteins uniquely elicit specific changes in the peptide backbone conformation that are reflected in the final folded states of the same peptide sequences in the native proteins in which they are found.
In subsequent years, Imperiali and her team tackled even more complicated glycosylation targets. For example, in they developed experiments to probe how glycosylation might “protect” proteins from misfolding by studying a modular domain of a prion protein (3).
She also helped to develop a system investigating how glycosylation influences not only the thermodynamic stability of proteins but also the mechanics of how it affects the process of reaching the folded state (4).
A source of inspiration at MIT has been the ribonucleotide reductase work of biochemist JoAnne Stubbe.
Imperiali explains, “The rigor and creativity with which she has tackled understanding the fundamental properties and reactivity of this central enzyme highlight the power of chemical and physical approaches in illuminating the details of really complex processes and drive me to take on the investigation of challenging problems in my own work.”
Dissection of an Archaeal Protein Pathway
Imperiali’s interest in the intricacies of protein glycosylation pathways led her and her colleagues to take on the challenge of dissecting the biochemical details of an archaeal pathway (5).
Archaea are single-celled microorganisms that often live in extreme conditions, such as at high temperatures or extreme acidity. Scientists have long puzzled over how the biochemical pathways of these microorganisms might be adapted to work under such conditions.
She says, “At first it seemed that the archaeal pathway that we were investigating was likely to be very similar to the corresponding pathway in other domains of life, but we started to find inconsistencies that suggested that there might be variations in the pathways for archaeal organisms that tend to exist under more extreme conditions.”
Imperiali and her team documented key differences in the specific biochemical details of the individual steps.
To this day, she and her team are still puzzling over the findings, but she says, “I believe that there is little doubt that there must be some good reason—perhaps from an evolutionary perspective—for the observed archaeal variations of the glycosylation pathway that we have characterized.”
Measuring and Manipulating Biochemical Processes
Another major component of Imperiali’s collaborative research involves studies concerning the design, development, and application of chemical approaches for measuring and manipulating biochemical processes.
She and her team constructed chemically caged phosphoamino acid building blocks for assembly into both peptides and proteins. They used this ability to rapidly and selectively release bioactive phosphopeptides and exploit these reagents in cellular studies focusing on DNA damage and cell cycle control, in collaboration with the group of Michael Yaffe at MIT (6).
Her group also developed a fluorescence-based method for sensing peptide and protein phosphorylation (addition of a phosphate group to a molecule) that could be used to monitor protein kinase activity.
Kinases are extremely important targets because they are involved in coordinating nearly all cellular activity. They often malfunction in disease states, such as cancer. Through interactions with colleagues at both MIT and other universities, Imperiali and her team fine-tuned the approach into a method that can screen kinase inhibitors and profile kinase activities in cell and tissue lysates (7, 8). “The approach that we developed has been commercialized, and we are now looking towards ways to further development of the methods for diagnostic applications,” she says.
Imperiali’s Inaugural Article speaks to a recurring theme in cellular glycan assembly processes (9).
Specifically, linear, long chain polyprenols are omnipresent molecular components in the biosynthetic pathways responsible for the assembly of essential glycoconjugates (carbohydrates covalently linked with other chemical species) including peptidoglycan and N-linked glycoproteins. Despite their highly conserved presence in all domains of life, the role of the extended polyprenyl groups in the dynamics of membrane-bound glycan assembly pathways remains a mystery.
“Certainly these components act as membrane anchors, but the physical length of the polyprenyl groups and the specific geometric features of the structures strongly suggest a far more sophisticated role,” Imperiali says.
InImperiali and her team established the foundation for this current work by assembling the enzymes and substrates required to ask questions about the structures and functions of the polyprenol linked substrates (10). The researchers were frustrated, however, by the membrane-associated nature of the enzymes in the pathways that they wanted to study, because the enzymes all required detergent solubilization for purification and analysis.
Six years ago, it was not possible to dissect the roles of the linear polyprenols in the sequential pathway processes in a native membrane environment. Over the last few years, however, Imperiali and her team overcame most of those challenges and are now able to simultaneously assess the interactions and activities of the polyprenyl-linked substrates, enzymes, and lipid bilayer. She says, “To me, this body of work finally establishes an experimental system that I believe will enable us to get to the real basis for the conservation of extended linear polyprenols in cellular glycoconjugate biosynthesis pathways.”
Imperiali’s work, looking at proteins in their living context, has applications for everything from drug development to diagnostics.
Her achievements have led to many honors, including the Protein Society Emil T. Kaiser Award and the American Chemical Society Breslow Award. She was elected to the American Academy of Arts and Sciences in and was admitted as a Fellow of the Royal Society of Chemistry in She earned Caltech and MIT's highest honors for teaching: inImperiali received Caltech's Richard P. Feynman Award for Excellence in Teaching, and inshe was named a Margaret McVicar Faculty Fellow in recognition of contributions to education at MIT.
Collaboration and teaching remain two of her greatest rewards.
Regarding the former, she says, “I really enjoy intense collaborative efforts where one has to stretch to cross boundaries and understand how expertise from a different discipline can shed light on a challenging problem that you have studied using techniques that you are familiar and comfortable with.” Imperiali’s pursuits in the laboratory are inseparable from her work in the classroom, which helps to fuel her research projects. She explains, “I love to teach!
I get so much energy from it.”
This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article on page
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