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Perspectives on building nanofactories for energy and medical uses

At the MSU-DOE Plant Research Laboratory (PRL), we are gathering scientists with varied areas of expertise to tackle key science problems through many angles – problems that are too large to address in single, isolated labs.

A major challenge, supported by the US Department of Energy's Office of Basic Energy Sciences, brings together 4 labs to understand, and, someday, build nanofactories, inspired by nature, to develop renewable energy sources addressing climate change or new chemicals for industrial or medical purposes.

Nanofactories in nature are found in many bacteria, and they have evolved to make a wide range of products, depending on the host’s needs. After all, bacteria that make these structures are highly diverse and found everywhere on the planet, from polar ice to scalding hot springs.

For example, one nanofactory produces energy out of carbon dioxide and sunlight in bacteria that live in waters like oceans and alpine lakes.

Closeup of a cyanobacteria cell
Cyanobacteria, formerly known as "blue-green algae," are one of the types of bacteria we are studying. Each is 25 times smaller than a human hair, and their nanofactories (the two circles in the middle) help their hosts capture sunlight and CO2 to be converted into useful energy.
By Eric Young

Another, in gut bacteria, isolates a toxic molecule, a smart trick that protects the host from poisoning itself, while helping it beat out other competing bacteria.

Special protein walls

What makes these nanofactories distinct, compared to normal cellular processes, is that they are protected by walls made of protein. This isolates them into small compartments inside the hosts (hence the ‘official’ name: bacterial microcompartments, or BMCs for short), which comes with some perks:

  1. The wall controls what raw material (metabolites) comes in and what product comes out. This allows the cell to carefully control the reactions inside, with no unwanted interference.
  2. The wall concentrates all production in one space, like bringing all employees together on one car assembly line. That increases productivity and speed.

The PRL wants to eventually repurpose these nanofactories to make things they usually don’t in nature, like:

The first hurdle is figuring out how the protein wall is built.

“We know that all these nanofactory walls are made of three flavors of proteins found throughout nature: BMC-H, BMC-T, BMC-P” according to Eric Young, a grad student in the Ducat lab. “They all fit together, like Lego bricks, and just like Legos, they can be used to build many different types of structures.”

“If we can figure out how these different proteins interact with each other, we would have a “Lego-like” assembly toolbox for making custom nanofactories and other types of assemblies. Then we can tailor what types of applications we use them for.”

The shells that make up the nanofactories
Zooming into a bacterial nanofactory wall, each is made up of three types of proteins, BMC-H, BMC-T, and BMC-P, fitting together like Lego blocks.
By Eric Young

Nanofactories in different shapes for more functions

Just recently, the Kerfeld lab revealed our first view of the compartment wall and how the three types of Lego bricks fit together (see below). Understanding how the pieces of the wall fit together will help us tinker with how to build custom structures.

Figure of a bacterial microcompartment, in other words, a nanofactory

Related: [VIDEO] Our first ever look at bacterial organelle shells

But Eric and other members of the team are tackling this concept differently. Instead of studying all three proteins, they are looking into what would happen if the individual protein Lego bricks assembled by themselves, without the other flavors.

“This approach revolves around using individual proteins as a way to build different nanostructures inside of cells, as new assembly lines for diverse applications. They would look different from the main nanofactory compartment.”

In other words, the more options we have for building nanofactories, the more applications we can imagine.

Eric’s recent focus has been on the BMC-H brick.

“Originally, we thought all BMC-H Lego bricks would form these striking, large nanostructures when put together in a cell. This didn’t happen in the case of one type of BMC-H brick. These different BMC-H bricks assembled into some striking shapes, from tubes, rods, to even ‘Swiss rolls’ (think of a rolled-up carpet).”

This result is leading the team down a line of thinking that subtle differences in the bricks lead to changes in how they assemble. And something unique about each protein flavor leads to them forming different shapes.

BMH-C bricks create Swiss rolls, tubes, and sheets
Different BMC-H bricks (center) join together to create different stuctures, like "Swiss rolls," tubes, and sheets (edges). Scientists want to engineer these structures into molecular assembly lines for custom renewable energy or medical applications.
By Eric Young

Some of these subtle differences occur at the junctures where the individual bricks come together.

“For example, we used computer simulations, with help from Oak Ridge National Lab, to further investigate two of the BMC-H Lego bricks. Amazingly, the simulations suggest that the brick which assembled into tubes inside living cells, also preferred to associate at an angle in the simulations. This provides a clue as to why this particular BMC-H curls in on itself to form a tube when many of them are connected in a series.”

Eventually, the team hopes to codify what they like to call “design principles” – basically, a set of predictive rules for how the various Lego bricks like to assemble.

These principles would suggest how to accurately build new structures and design useful functions into them.

“For example, a tube shape could be used as a tiny pipeline inside the cells, allowing raw precursors to flow in and products—like biofuels or medicines—to flow out,” Eric says.

Or, he adds, structures like rods and sheets could be used as surfaces to program new function into the cells – think like little molecular switchboards!

“We have already made some good strides by realizing that subtle differences can change how the individual blocks assemble. Now, we are using knowledge of the structure of the protein to change properties of the blocks, in a “design, build, test, repeat” cycle, to tease out the rules of assembly.”

Banner image: Huge mats of brilliant bacteria and algae live on the edges of this hot spring, in this aerial photo from Yellowstone National Park. Some of these organisms contain special nanofactories that help them survive in the extreme heat; By Jim Peaco, National Park Service, Public Domain.
This work was primarily funded by the US Department of Energy, Office of Basic Energy Sciences. Eric’s paper is published in Frontiers in Microbiology under a special issue of “Novel Metabolic Engineering Approaches for Producing Novel Chemicals.”

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