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The Intrigue of Integral Membrane Proteins

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Christine Wu
Title: Assistant Professor, University of Colorado Denver School of Medicine
Education: PhD, University of Colorado Health Sciences Center, 2001
Recommended by: John Yates

As a self-proclaimed "hybrid cell biology/mass spectrometry person," Christine Wu puts her background to good use in her lab. At the University of Colorado School of Medicine, Wu uses proteomic technology to characterize integral membrane proteins. It's a niche field, she says, because not a lot of scientists are focusing on this brand of protein. "Most proteomic methods are targeted toward, in general, all proteins, and, in particular, soluble proteins," she says. "[But] we like to look at the ones that are embedded in the lipid bilayer, number one, because they're challenging and, number two, because they are basically the majority of the drug targets."

In her lab, Wu uses shotgun proteomic methods to build upon the lack of structure information for these proteins. "Right now, there are no crystal structures available for most of these targets, and the reason why is because they're very, very difficult to crystallize — they're sitting in lipid bilayers and they're amphipathic," she says, adding that the question is, "How do we get a huge amount of information on the topology of these integral membrane proteins that will then supplement what's lacking in the structural world?"

Though she got her PhD in cell biology, Wu says her hard-earned DIY philosophy came from having to build the mass spec tools she needed to perform the research she was interested in during her postdoc with John Yates at Scripps. At the time, the method of choice was 2D gels, which aren't good at resolving membrane proteins. "I had started a collaboration with John Yates because he had been working up some novel methods, in particular the MudPIT approach. I was complaining to him about this sort of disconnect between cell biology and what's required and what was available," she says. She joined his lab because she wanted to focus on membrane proteins, despite the lack of technology. In fact, being among both groups has definitely influenced the way she approaches her research. "I think in terms of a cell biologist, [but] I apply everything sort of analytically through the eyes of a mass spectrometrist," she says.

Because of the dual nature of her work, one of the biggest challenges is trying to maintain a level of expertise in both areas; for her, she's lucky to be surrounded by people from both fields in a collaborative environment at the University of Colorado. "I want to do both, and so I have to get the resources for both, and that's quite a challenge," Wu says.

Looking ahead

In general, she sees the field of proteomics moving towards diagnostics. The past 10 years have been spent, she says, "profiling, [or] accumulating lists. I think the next phase — and we're starting to get into that phase right now — is development of these diagnostic assays where you have your list of [biomarker] targets and then you have to go in and actually validate them in some type of clinical assay."

In her own work, Wu will continue to build knowledge around the structure and function of integral membrane proteins. Using a "protease accessibility map, we're able to then target certain domains to serve as a proxy for the conformational change that's happening in these integral membrane proteins, and then, we'd be able to use targeted analysis to assess the conformation of these [proteins]," she says.

Publications of note

In 2008, Wu published a paper in the Journal of Proteome Research that describes a shotgun proteomic method for analyzing the transmembrane domains of integral membrane proteins. Mapping uncharted territory of the proteome, as she did in this work, is one of the drivers behind her research, Wu says.

And the Nobel goes to...

If she won the Nobel, Wu says, it would be because "the contribution of this technology led to advances in biomedical research — in biomarker discovery, in drug targets."

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