How much difference can a tenth of a nanometer make? When it comes to figuring out how proteins work, an improvement in resolution of that miniscule amount can mean the difference between seeing where atoms are and understanding how they interact.
Case in point: New, improved-resolution views of a zinc transporter protein deciphered at the U.S. Department of Energy's Brookhaven National Laboratory provide not just a structure but also a suggested mechanism for how cells sense and regulate zinc, an element that is essential for life, but which must be kept at a steady state to avoid problems like seizures, diabetes, and possibly Alzheimer's disease.
The new findings, to be published online on September 13, 2009, by Nature Structural & Molecular Biology, also suggest targets for zinc-regulating drugs, and may even advance the understanding of similar zinc-regulating enzymes in plant chloroplasts with possible implications for biofuel production.
"Our goal is to reveal atomic interactions in a protein structure to understand the chemistry that underlies the protein's biological function," said Brookhaven biologist Dax Fu, who led the research. "With this structure, we can begin to understand the mechanism of zinc transport at a chemical level."
The structure was revealed using x-ray crystallography at Brookhaven Lab's [http://www.nsls.bnl.gov/] National Synchrotron Light Source (NSLS), a source of intense x-ray, ultraviolet, and infrared light. By studying how x-rays bounce off crystallized samples of a protein, scientists can reconstruct the location and orientation of the protein's atoms in three dimensions.
The Brookhaven team had previously used NSLS to solve a zinc transporter protein structure at lower resolution*. To achieve the new-and-improved structure, the scientists added mercury atoms to stabilize protein packing in the crystals. This increased the resolution of their x-ray vision by a mere angstrom (tenth of a nanometer). But because it brought the overall resolution of their structure to just below 3 angstroms — the point at which individual atoms begin to become visible — it enabled the scientists to see the protein in action as it bound to and transported zinc ions.
Using fluorescent probes, the scientists also studied how the protein changed shape in response to zinc binding. And they tested how changes to structural elements of the zinc transporter protein would affect its ability to transport zinc.
Together, these experiments suggest an auto-regulatory mechanism for zinc transport: Zinc binding within the cell triggers hinge-like movements of two electrically repulsive portions of the protein that lie within the cell's interior, which results in a conformational change in the portion of the protein that traverses the cellular membrane. So when zinc levels inside the cell rise too high, this shape shifting somehow pushes zinc ions through the membrane and out of the cell.
"Exactly how the protein pushes the zinc ions through the membrane has yet to be determined," said Fu, who added that this will be a focus of future research.
Conceivably, he added, drugs that bind to the zinc-sensing portions of the protein could be used to modulate zinc transport activity and help adjust zinc levels as possible treatments for diseases such as seizure disorders or diabetes. Brookhaven Science Associates, which manages Brookhaven Lab, has filed a patent application related to this work.
In addition, because other metal transporting proteins share similar architecture with the zinc transporter protein, the findings from this study may advance the understanding of other medical disorders linked to metal imbalance, as well as the development of possible treatments for those conditions.
Furthermore, this work may have implications for researchers trying to improve the prospects of biomass production in plants, an essential component to the development of biofuels. Zinc is an essential co-factor in a host of reactions in chloroplasts, the site of photosynthesis. But as is the case in animals, excess metals can be highly toxic in plants. Consequently, studies to help elucidate zinc-transporter protein function could help scientists understand how plants maintain the delicate balance needed for ideal growth.
Future studies of protein structures at Brookhaven Lab promise to reveal even greater mechanistic detail when a new light source, known as NSLS-II, opens in 2015. That facility, now under construction, will be 10,000 times brighter than NSLS. That boost in brightness — and therefore resolution — would be particularly important in the study of membrane proteins, which represent the vast majority of proteins of interest to those developing drugs, but which are also often difficult to crystallize.
"As illustrated by this study, even small improvements in x-ray diffraction resolution can greatly advance our mechanistic understanding of protein function," said Fu.
This research was performed at beamline X25A at the NSLS. The work was supported by the National Institutes of Health, DOE's Office of Science (Office of Basic Energy Sciences), and by the Biology Department at Brookhaven Lab.
* Previous News Release: Zinc Transporter Protein Structure Deciphered: http://www.bnl.gov/bnlweb/pubaf/pr/PR_display.asp?prID=07-89
One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.
Visit Brookhaven Lab's electronic newsroom for links, news archives, graphics, and more: http://www.bnl.gov/newsroom
Karen McNulty Walsh | EurekAlert!
A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich
New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
20.02.2017 | Materials Sciences
20.02.2017 | Health and Medicine
20.02.2017 | Health and Medicine