May 11, 2007

Aliquots — Research highlights from VUMC laboratories

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Staph senses iron to know it’s in

Staphylococcus aureus, one of the most significant infectious threats to public health, lives harmlessly on the skin or in the noses of about 25 percent of the human population. To initiate an invasive infection, S. aureus must “sense” that it has gained access to internal tissues or blood vessels. It appears to do this by recognizing iron-containing heme in proteins like hemoglobin and myoglobin.

In the April issue of Cell Host & Microbe, Eric Skaar, Ph.D., and colleagues describe an S. aureus heme sensor system (Hss) that responds to heme and activates expression of the heme-regulated transporter (Hrt). The investigators propose that the coordinated activity of Hss and Hrt allows S. aureus to sense internal host tissues and modulate its virulence to avoid excessive tissue damage. Genomic analyses identified related systems in other Gram-positive bacteria, suggesting a conserved strategy for host recognition and virulence control. Identifying such systems could lead to the development of novel therapeutics targeting bacterial gene regulation.

— Leigh MacMillan

‘BAC’ to functional genetics

Identifying disease-associated mutations is an important first step in understanding disease processes, but determining the functional relevance of those mutations can be difficult.

To facilitate such studies, Angela Eeds, Ph.D., Marshall Summar, M.D., and colleagues developed a new tool based on bacterial artificial chromosomes (BACs) and used it to examine the effects of four mutations linked to carbamyl phosphate synthetase I (CPSI) deficiency — a rare metabolic disorder that can cause dangerously high levels of ammonia in the blood.

Using this system, the researchers determined that all four CPSI mutations — even one previously considered benign — cause splicing or RNA processing defects. The results, reported in the April issue of The American Journal of Human Genetics, add to the increasing evidence that many apparently “silent” mutations affect RNA processing, which may represent an important disease mechanism. And since the BAC-based system is flexible, this new tool could help identify the functional effects of a wide range of genetic variants, the authors suggest.

— Melissa Marino

The shape of the G protein switch

G proteins serve as molecular “switches” for a vast array of biological responses. They pass information from receptors at the cell surface — targets for about half of all currently prescribed drugs — to effector molecules inside the cell. How G proteins cycle between “off” and “on” has been under intense investigation.

William Oldham, Ph.D., Heidi Hamm, Ph.D., and colleagues now describe a pathway of shape changes in the G protein alpha subunit that are triggered by receptor binding. The investigators used site-directed spin-labeling and EPR spectroscopy to study the “switch I” region in G-alpha-i, allowing them to detect dynamic changes in the protein structure. The study, published May 8 in Proceedings of the National Academy of Sciences, provides structural data for four conformations of G-alpha-i, including the complex between the “empty” G protein heterotrimer and the activated receptor. The structure of this complex, for which no crystal structure has been reported, is critical to understanding how receptors flip the G protein switch.

— Leigh MacMillan

Muscles’ finer details in view

Our knowledge about muscle architecture comes primarily from cadaver dissection and, more recently, ultrasound. While both techniques are limited in their ability to provide an accurate and detailed representation of an entire muscle's architecture, diffusion-tensor magnetic resonance imaging (DT-MRI), which tracks nerve and muscle fibers based on water diffusion down the length of the fiber, may be able to distinguish the finer features of muscle structure.

In the April 19 online edition of the Journal of Applied Physiology, Bruce Damon, Ph.D., and colleagues report the feasibility of using DT-MRI in humans to track muscle fibers and provide a high-resolution characterization of muscle architecture. The researchers measured muscle pennation angles — the angles at which the muscle fibers attach to their tendon — of a shin muscle, the tibialis anterior. This method, applicable to a wide range of muscles, may provide an important non-invasive tool for investigating muscle architecture in health and disease, the researchers report.

— Melissa Marino

We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to:

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012