Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Antibacterial protein’s molecular workings revealed

22.02.2013
On the front lines of our defenses against bacteria is the protein calprotectin, which “starves” invading pathogens of metal nutrients.
Vanderbilt investigators now report new insights to the workings of calprotectin — including a detailed structural view of how it binds the metal manganese. Their findings, published online before print in the Proceedings of the National Academy of Sciences, could guide efforts to develop novel antibacterials that limit a microbe’s access to metals.

The increasing resistance of bacteria to existing antibiotics poses a severe threat to public health, and new therapeutic strategies to fight these pathogens are needed.
The idea of “starving” bacteria of metal nutrients is appealing, said Eric Skaar, Ph.D., MPH, associate professor of Pathology, Microbiology and Immunology.

In a series of previous studies, Skaar, Walter Chazin, Ph.D., and Richard Caprioli, Ph.D., demonstrated that calprotectin is highly expressed by host immune cells at sites of infection. They showed that calprotectin inhibits bacterial growth by “mopping up” the manganese and zinc that bacteria need for replication.

Now, the researchers have identified the structural features of calprotectin’s two metal binding sites and demonstrated that manganese binding is key to its antibacterial action.

Calprotectin is a member of the family of S100 calcium-binding proteins, which Chazin, professor of Biochemistry and Chemistry, has studied for many years. Chazin and postdoctoral fellow Steven Damo, Ph.D., used existing structural data from other S100 family members to zero in on calprotectin’s two metal binding sites. Then, they selectively mutated one site or the other.

They discovered that calprotectin with mutations in one of the two sites still bound both zinc and manganese, but calprotectin with mutations in the other site only bound zinc.

The researchers recognized that these modified calprotectins — especially the one that could no longer bind manganese — would be useful tools for determining the importance of manganese binding to calprotectin’s functions, Chazin noted.

Thomas Kehl-Fie, Ph.D., a postdoctoral fellow in Skaar’s group, used these altered calprotectins to demonstrate that the protein’s ability to bind manganese is required for full inhibition of Staphylococcus aureus growth. The investigators also showed that Staph bacteria require manganese for a certain process the bacteria use to protect themselves from reactive oxygen species.

“These altered calprotectin proteins were key to being able to tease apart the importance of the individual metals — zinc and manganese – to the bacterium as a whole and to metal-dependent processes within the bacteria,” Skaar said. “They’re really powerful tools.”

Skaar explained that calprotectin likely binds two different metals to increase the range of bacteria that it inhibits. The investigators tested the modified calprotectins against a panel of medically important bacterial pathogens.

“Bacteria have different metal needs,” Skaar said. “Some bacteria are more sensitive to the zinc-binding properties of calprotectin, and others are more sensitive to the manganese-binding properties.”

To fully understand how calprotectin binds manganese, Damo and Chazin — with assistance from Günter Fritz, Ph.D., at the University of Freiburg in Germany — produced calprotectin crystals with manganese bound and determined the protein structure. They found that manganese slips into a position where it interacts with six histidine amino acids of calprotectin.

It’s really beautiful; no one’s ever seen a protein chelate (bind) manganese like this,” Chazin said.“It’s really beautiful; no one’s ever seen a protein chelate (bind) manganese like this,” Chazin said.

The structure explains why calprotectin is the only S100 family member that binds manganese and has the strongest antimicrobial action, and it may allow researchers to design a calprotectin that only binds manganese (not zinc). Such a tool would be useful for studying why bacteria require manganese — and then targeting those microbial processes in new therapeutic strategies, Chazin and Skaar noted.

“We do not know all of the processes within Staph that require manganese; we just know if they don’t have it, they die,” Skaar said. “If we can discover the proteins in Staph that require manganese — the things that are required for growth — then we can target those proteins.”

The team recently was awarded a five-year, $2 million grant from the National Institute of Allergy and Infectious Diseases (AI101171) to advance their studies of calprotectin and how it works to limit bacterial infections and in other inflammatory conditions.

“Nature stumbled onto an interesting antimicrobial strategy,” Chazin said. “Our goal is to really tease apart the importance of metal binding to all of calprotectin’s different roles — and to take advantage of our findings to design new antibacterial agents.”

The research was supported by grants from the National Institutes of Health (CA009582, HL094296, AI091771, AI069233, AI073843, GM062122). Skaar holds the Ernest W. Goodpasture Chair in Pathology; Chazin holds the Chancellor’s Chair in Biochemistry and Chemistry and is director of the Vanderbilt Center for Structural Biology.
Contact:
Leigh MacMillan, (615) 322-4747
leigh.macmillan@vanderbilt.edu

Leigh MacMillan | EurekAlert!
Further information:
http://www.vanderbilt.edu

More articles from Life Sciences:

nachricht The first genome of a coral reef fish
29.09.2016 | King Abdullah University of Science and Technology

nachricht New switch decides between genome repair and death of cells
27.09.2016 | University of Cologne - Universität zu Köln

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New welding process joins dissimilar sheets better

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...

Im Focus: First quantum photonic circuit with electrically driven light source

Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.

Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

HLF: From an experiment to an establishment

29.09.2016 | Event News

European Health Forum Gastein 2016 kicks off today

28.09.2016 | Event News

Laser use for neurosurgery and biofabrication - LaserForum 2016 focuses on medical technology

27.09.2016 | Event News

 
Latest News

New Multiferroic Materials from Building Blocks

29.09.2016 | Materials Sciences

Silicon Fluorescent Material Developed Enabling Observations under a Bright “Biological Optical Window”

29.09.2016 | Materials Sciences

X-shape Bio-inspired Structures

29.09.2016 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>