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Investing in the Future
CHORI Lab Identifies for the First Time a Unique Helical Structure for Apolipoprotein A-V

"In order to understand how any protein functions at a mechanistic level, it's import-ant to under-stand how the protein is organ-ized. Although we've learned a great deal about apoA-V already, we didn't know that much about its N-terminal region," explains Dr. Ryan.

Although CHORI is a free-standing research institute not affiliated with any university, CHORI and its researchers are committed to educating the next generation of scientists, as Robert Ryan, PhD, of CHORI’s Center for the Prevention of Obesity, Diabetes and Cardiovascular Disease, has been doing for the past 5 years in his capacity as Adjunct Professor in the Department of Nutritional Science and Toxicology at the University of California, Berkeley.

Dr. Ryan’s latest protégé, Kasuen Wong, has just had her 3rd publication come out in the August issue of Biochemistry, in which, along with Dr. Ryan and their colleagues, Ms. Wong reveals that the N-terminus of apolipoprotein A-V (apoA-V) adopts a helix bundle motif. This is the first time a helix bundle structure has been reported for apoA-V and provides new insight into the potential mechanism by which apoA-V could transition from a hydrophilic soluble conformation to an extended open conformation appropriate for lipid binding.

As Ms. Wong and Dr. Ryan explain, apoA-V was first identified in 2001, with subsequent research indicating that this particular apolipoprotein is strongly correlated with the modulation of plasma triglyceride (TG) levels.

"People are very interested in plasma triglyceride levels because they are an important determinant of an individual's risk for cardiovascular disease, obesity and diabetes," Dr. Ryan says. "Our lab has been interested in trying to understand how apoA-V actually modulates triglyceride levels in plasma."

Now in her 4th year of graduate studies, Ms. Wong, who is supported by the Gates Millennium Scholarship, has been instrumental in helping the Ryan lab elucidate elements of apoA-V that are key to understanding its ability to modulate plasma TG levels. In fact, Ms. Wong presented the research on which the Biochemistry publication is based this summer at the biannual Gordon Research Conference on Lipoprotein Metabolism.

Using primarily biochemical methods, as opposed to in vivo studies, Ms. Wong and Dr. Ryan were able to provide enough evidence to conclude that the N-terminus of apoA-V adopts a helix bundle motif. Particularly compelling was the solubility of the apoA-V N-terminal segment in comparison to full-length apoA-V, which is insoluble at physiological pH in the absence of lipid.
"Exchangeable apolipoproteins are a unique class in the protein world in that they have to exist in two very different environments, one that is hydrophobic and one that is not," explains Ms. Wong.
"The helix bundle formation allows apoA-V to put its hydrophobic surfaces into its core to allow solubility in the absence of lipid and to expose those surfaces when it binds to lipoproteins."

In order to get closer to identifying the ways in which this particular apolipoprotein might be modulating TG levels, Ms. Wong is continuing her biochemical investigations by exploring how the helix bundle interacts with lipid surfaces. If Ms. Wong is any indication, CHORI's investment into the future of scientific research is paying off in spades.

"Kasuen's truly a remarkable individual," says Dr. Ryan. "She's a critical thinker, inquisitive and determined to succeed. She's well on her way to becoming a successful independent biomedical researcher, if that's what she decides to do."
For her part, Ms. Wong plans to pursue a post-doctoral research position and hopes to stay in the field of lipid metabolism.

"I'd like to continue with research that relates to obesity, Type 2 diabetes and cardiovascular disease," Ms. Wong says. "I like the idea of doing work that will have a social impact."

In the mean time, Ms. Wong isn't slowing down at all, but is currently working with Dr. Ryan to pursue NIH funding to take the apoA-V studies to the next step by investigating whether or not this N-terminal fragment is both necessary and sufficient to elicit TG-lowering effects in the in vivo setting.

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Tuesday, May 17, 2011 8:19 AM

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