Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Antibacterial protein’s molecular workings revealed

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.
Leigh MacMillan, (615) 322-4747

Leigh MacMillan | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

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 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>