Faculty Spotlight: The Department of Chemistry Welcomes Bill Wuest

Bill WuestThe Department of Chemistry at Emory University is pleased to welcome Bill Wuest to our faculty beginning in June 2017. Dr. Wuest joins Emory from Temple University where he was Daniel Swern Early Career Professor of Chemistry. At Emory, he will be the first Georgia Research Alliance (GRA) Distinguished Investigator in Emory College of Arts and Sciences. He will be joined at Emory by six graduate students–Erika Csatary, Colleen Keohane, Kelly Morrison, Sean Rossiter, Amy Solinski, Andrew Steele–and postdoc Sara Zahim.

Bill was born in Centereach, NY in 1981. He received his B.S. magna cum laude in Chemistry/Business from the University of Notre Dame in 2003. As an undergraduate, he investigated intramolecular hydroamination reactions under the tutelage of Professor Paul Helquist. Bill then moved to Philadelphia, PA to begin his graduate studies at the University of Pennsylvania working with Professor Amos B. Smith, III. His graduate work focused on both the total synthesis of peloruside A and the development of Anion Relay Chemistry (ARC) culminating with a Ph.D. in 2008. Bill then traveled to Harvard Medical School as a Ruth Kirschstein-NRSA Postdoctoral Fellow in the laboratory of Professor Christopher T. Walsh, where he investigated unusual enzymatic transformations in the construction of non-ribosomal peptide natural products.

In July of 2011, Bill began his independent career as an Assistant Professor at Temple University. His research focuses on the development of chemical tools to better understand bacteria with a specific focus on anti-virulence targets and narrow-spectrum therapeutics. He is also a member of the Molecular Therapeutics Division of Fox Chase Cancer Center and the Scientific Founder of NovaLyse BioSolutions, which seeks to commercialize the QAC technology developed in collaboration with the Minbiole Group at Villanova University. Bill is the recipient of a number of awards including the NIH ESI Maximizing Investigators Research Award (MIRA), NSF CAREER Award, the Young Investigator Award from the Center for Biofilm Engineering at Montana State University, the New Investigator Award from the Charles E. Kaufman Foundation, the Thieme Journal of Chemistry Award, and the Italia-Eire Foundation Distinguished Teacher of the Year Award from the College of Science and Technology at Temple University.

Bill is an avid sports fan, with allegiances to the NY Yankees, NY Giants, and his alma mater, the Notre Dame Fighting Irish. Outside the lab he enjoys spending time with his wife, Liesl, and son, Max.

Faculty Spotlight: Khalid Salaita

Khalid Salaita. Photo by Jessica Lily Photography.
Khalid Salaita. Photo by Jessica Lily Photography.

Last spring, Assistant Professor Khalid Salaita‘s lab was awarded a grant from the National Institute of General Medical Science (part of the NIH) to study the Notch signaling pathway and develop techniques to look at the forces applied at the interface of cell membranes. Originally named for its role in the formation of notched Drosophila wings, the Notch receptor play a crucial role in cell to cell communication, cell development and differentiation.  Mutations in this transmembrane protein result in dysfunction of the entire pathway, which can lead to various types of cancers including T-cell acute lymphoblastic leukemia (T-ALL).  Because Notch is so crucial in cell differentiation, having too much or too little present in the membrane can also cause tumor growth.

Notch’s ligand-binding domain exists outside the cell membrane and when it locates a ligand molecule on the surface of an adjacent cell they bind, and the signal pathway begins.  Once the ligand is bound, a protease comes in and snips off the extracellular domain from the transmembrane domain.  However, the site that gets cut is buried within the folded protein, suggesting there must be a conformational change to allow access to the site.  The Salaita Lab hypothesizes this conformational change occurs via a mechanical force; the cell pulling back on Notch, exposing the cleavage site.  Their lab is working on tagging ligands with chromophores and quenchers so they can use fluorescence to see the protein stretching as it is being pulled by the cell. By calibrating the fluorescence of a given chromophore/quencher pair to the amount of force being applied to stretch them apart, they can quantitatively look at mechanical force exerted by the cell.

The Notch receptor with a green fluorescent protein tag on the intracellular domain is overexpressed in mammalian cells and seeded onto a membrane surface functionalized with the ligand (DLL4-mCherry). The two proteins bind and the extracellular domain gets snipped, the domain inside the cell can then be cut and act as a transcription factor, starting the signaling pathway. (Fig. 1)

By labeling the ligand and Notch with fluorescence tags they can not only establish that the two are binding based on the overlap (Fig 2), but by studying the intensity of the fluorescence, they can determine the density of molecules at the interface and their binding stoichiometry.

Unlike other membrane proteins that have been more heavily studied, only parts of the Notch structure are known by either NMR or X-ray crystallography, which makes it even more difficult to work with.  The Salaita lab is up for the challenge though: “Having a five year grant allows you to take a breath and really dive in to solving some hard problems,” said Salaita.

Notch receptor mechanotransduction could be just the tip of the iceberg, there could be thousands of other receptors where a similar mechanism could be in play.  Developing the methodology to explore these forces will open up new avenues for understanding and ultimately controlling membrane proteins and the diseases to which they contribute.

Faculty Spotlight: Chris Scarborough

Faculty Spotlight: Emily Weinert

Q: What made you decide to major in chemistry?

EW: My dad’s a physicist. I grew up spending time thinking about `here’s the natural world, what’s going on’ kind of questions-so I love science. And I just really like the molecular level understanding, trying to really understand. In college, I loved organic chemistry because once you understand what’s happening, it can be predictive. I love being able to do the experiments, have a prediction, go in test it and ask “Does that make sense?”.

Q: What made you transition to biomolecular chemistry?

EW: I’ve always really been interested in living systems and trying to sort out what’s happening in these complex systems. I had always hoped to get to the part in my Ph.D. (working with quinone methides) where we’d learned enough to go in vivo and test some of our theories. But like so often happens in science, sometimes you find that you really don’t understand things that well or you get drawn in different paths-so I wanted to do something more biological after focusing on small molecules.

Q: Did you ever want to be anything else?

EW: Actually, when I was growing up I wanted to be a wildlife biologist.

Q: Really?

EW: Yeah, live out in the wild and count the wolves and watch their migration patterns… But then I realized I didn’t really like the cold that much and living out in a tent with things that could eat me makes me a little nervous so I ran for the lab instead. I think it worked out a lot better.

Q: And you have, like, you know…plumbing

EW: Yeah, (laughs) that was another thing.

Q: What research does your lab focus on?

EW: My lab does protein chemistry. We’re interested in understanding how proteins work, thinking about them as complex chemical systems rather than as the normal circles and pac-men that we often see.

The two general interests in the lab are heme proteins and nucleotide signaling. We have some proteins that are heme proteins and some proteins that are involved in nucleotide signaling and at the intersection are a group of proteins that have both heme domains and do nucleotide chemistry. We’re looking at cyclic nucleotide signaling in bacteria and some potentially new cyclic nucleotides that are involved in pathways in mammals.

We’re also interested in heme proteins and how protein scaffolds tune the electronics and the reactivity of the heme itself. A lot of heme proteins use protoporphyrin IX, although there are some other porphyrins, but you can take protoporphyrin IX and do chemistry with oxygen, like peroxidases and P450 enzymes. And you can also use the same porphyrin to do reversible ligand binding for oxygen delivery or for sensing. So organisms can actually sense gases, binding very low concentrations of ligand so that it causes a downstream change in the organism.

Q: And this variation in activity is dependent on the protein structure?

EW: Yes, the scaffold itself. So you can change the redox potential widely from around -400 mV to around 380 mV. That’s a huge change. You can change the type of reaction; you can change if you can do electron transfer with most of the biologically available oxidants and reductants. And so it can changes just about everything. And right now, our understanding of that is still pretty poor. There’s a huge amount of work that’s been done on the globins. I think there are probably at least 150 mutants of myoglobin that have been published, but it’s still not very predictive and we can’t always apply it to other heme proteins. So, like most protein engineering or protein chemistry, we don’t have a lot of predictive power to suggest how mutations will affect the heme.

Q: Which chemist do you wish you had an opportunity to meet?

EW: Rosalind Franklin and Hans Fischer.

Q: Why them?

Rosalind Franklin has a fascinating story. The work she was doing was still in a time when it was not necessarily expected that many women did their own science. She was clearly brilliant and she figured out most of the structure of DNA before Watson and Crick. The reason Watson and Crick got the structure was by looking at her data. Unfortunately she died before the Nobel Prize was given and they don’t give it posthumously. I think she would be fascinating to talk to and to hear her story.

Hans Fischer was the first to discover chlorophyll and heme and he was the first one to figure out what these pigments were and to synthesize them. I think it’s really interesting to think of how do you go about, at the time (the 1920’s), saying `I’m going to isolate this colored compound’ and then how do you go about with the techniques then available figuring out what all is in there? I think it would be really interesting to hear how the field got started from the guy that started the field!