SEP 08, 2015 04:48 PM PDT

Revealing Protein Structure

Researchers at the University of Pennsylvania have developed a new method of gene sequencing a strand of DNA’s bases and reading them as they are threaded through a nanoscopic hole. Their study shows that this technique can also be applied to proteins as way to learn more about their structure.
Nanoscopic threading reveals protein structure. 
Current methods for such analysis are labor intensive, typically involving the collection of large quantities and modifying the protein, limiting the ability to understand how the protein behaves in its natural state. The Penn researchers’ translocation technique enables the study of individual proteins without modifying them. Analysis of samples taken from a single individual this way could open up applications for disease diagnostics and research.  
 
Led by Marija Drndi?, a professor in the School of Arts & Sciences’ Department of Physics & Astronomy; David Niedzwiecki, a postdoctoral researcher in her lab; and Jeffery G. Saven, a professor in Penn Arts & Sciences’ Department of Chemistry, the study was published in the journal ACS Nano and reported in Bioscience Technology
 
The technique comes from Drndi?’s work on nanopore gene sequencing, which tries to distinguish the bases in a strand of DNA by the different percentage of the aperture they each block as they pass through a nanoscopic pore. Different silhouettes enable different amounts of an ionic liquid to pass through the pore. Electronics surrounding the pore measure the change in ion flow. The peaks and valleys of that signal can be correlated to each base.
 
While researchers work to increase the accuracy of these readings to useful levels, Drndi? and her colleagues have experimented with applying the technique to other biological molecules and nanoscale structures. Collaborating with Saven’s group, they set out to test their pores on even trickier biological molecules.
 
Saven explained, “There are many proteins that are much smaller and harder to manipulate than a strand of DNA that we’d like to study. We’re interested in learning about the structure of a given protein, such as whether it exists as a monomer, or combined with another copy into a dimer, or an aggregate of multiple copies known as an oligomer.”
 
Detection is also often a limitation, according to Drndi?, who explained, “There are no ways to amplify peptides and proteins like there are for DNA. If you want to study proteins from a particular source, you're stuck with very small samples. With this method, however, you can just collect the amount of data you need and the number of proteins you want to pass through the pore and then study them one at a time as they naturally exist in the body.”
 
Using the Drndi? group’s silicon nitride nanopores, which can be drilled to custom diameters, the research team set out to test their technique on GCN4-p1, a protein selected because it contains a common structural motif found in transcription factors and intracellular receptors. The Penn researchers put different ratios of zipped and unzipped versions of the protein in an ionic fluid and passed them through the pores. Although they could not tell the difference between individual proteins, the researchers could perform this analysis on populations of the molecule.
 
“The dimer and monomer form of the protein block a different number of ions, so we see a different drop in current when they go through the pore,” Niedzwiecki said. “But we get a range of values for both, as not every molecular translocation event is the same.”
 
Saven concluded, “Many researchers have observed these long tangles of aggregated peptides and proteins in diseases like Alzheimer’s and Parkinson’s, but there is an increasing body of evidence that is suggesting these tangles are occurring after the fact, that what are really causing the problem are smaller protein assemblies. Figuring out what those assemblies are and how large they are is currently really hard to do, so this may be a way of solving that problem.”
 
About the Author
  • Ilene Schneider is the owner of Schneider the Writer, a firm that provides communications for health care, high technology and service enterprises. Her specialties include public relations, media relations, advertising, journalistic writing, editing, grant writing and corporate creativity consulting services. Prior to starting her own business in 1985, Ilene was editor of the Cleveland edition of TV Guide, associate editor of School Product News (Penton Publishing) and senior public relations representative at Beckman Instruments, Inc. She was profiled in a book, How to Open and Operate a Home-Based Writing Business and listed in Who's Who of American Women, Who's Who in Advertising and Who's Who in Media and Communications. She was the recipient of the Women in Communications, Inc. Clarion Award in advertising. A graduate of the University of Pennsylvania, Ilene and her family have lived in Irvine, California, since 1978.
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