It's a stitchup: Evolving new proteins

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  • Published: May 15, 2016
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: It's a stitchup: Evolving new proteins

Critical direction

Design of structurally distinct proteins using strategies inspired by evolution Credit: Christ-claude Mowandza-ndinga, UNC Health Care

Scientists in the USA are stitching together novel proteins from fragments of natural proteins in an evolutionary manner and using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to examine the results.

Proteins are the machinery, the sensors and the catalysts of the cell and when they go awry disease can ensue. Research published in the journal Science by a team from the University of North Carolina School of Medicine has opened up a new route to the design of new proteins that might be used to model natural proteins and uncover new ways to service the cellular machinery in disease.

The new technique, dubbed "SEWING", was inspired by the natural processes of evolution in which portions of proteins can blend to produce new structures with new functions. SEWING allows the team to generate a diverse set of protein structures with many of the distinctive features that proteins require to carry out specific biological functions. They have the potential to be developed into therapeutic agents themselves or be used as catalysts and biosensors too.

"We can now begin to think about engineering proteins to do things that nothing else is capable of doing," explains the paper's senior author Brian Kuhlman who is a member of the UNC Lineberger Comprehensive Cancer Center. "The structure of a protein determines its function, so if we are going to learn how to design new functions, we have to learn how to design new structures. Our study is a critical step in that direction and provides tools for creating proteins that haven’t been seen before in nature."

Had them in stitches

Fundamentally, proteins are just hundreds or thousands of amino acids strung together to form long chains the chemistry of which then leads to the folding of the chain into its functional form. Sequence is everything ultimately determining the unique geometry of each protein. The fan-like beta-pleated sheets, the self-referential curve of the alpha helix and the many other motifs give us the 100,000 or so proteins in our bodies present because of millions of years of evolution. Each pleat, coil and cavity evolved for a specific task in the cell.

Computational protein design has been used to recreate what exists naturally, but the aim has always been to find new protein structures that might have novel functionality. Kuhlman and his colleagues believe that by removing the limitations of the pre-determined blueprints used in earlier studies and taking a cue from evolution they can more easily construct new and functional proteins.

Their computer strategy, whimsically named SEWING is spelled out as Structure Extension With Native-substructure Graphs). In this technique, the researchers started with a slew of naturally occurring proteins and chopped them up, in silico, into well-defined pieces, the common motifs of protein tertiary structure. They then stitches the bits and pieces together in different ways to see which would sit well with the others and in what combinations. In nature, this would occur through evolutionary processes in the computer the process involved searching for regions of structural similarity that normally work together.

Finding the needle

Team member Tim Jacobs used the method to map out 50,000 of these stitched together proteins on the computer. He then tapped a number of different metrics to whittle down the list to a top 21 proteins that could be synthesised and then investigated using crystallography and NMR spectroscopy. The analytical work showed that the proteins contained all the unique structural motifs that the team had designed on the computer and in the right order.

"We were excited that some had clefts or grooves on the surface, regions that naturally occurring proteins use for binding other proteins," explains Jacobs. "That's important because if we wanted to create a protein that can act as a biosensor to detect a certain metabolite in the body, either for diagnostic or research purposes, it would need to have these grooves. Likewise, if we wanted to develop novel therapeutics, they would also need to attach to specific proteins."

The team is now using SEWING to stitch together proteins that could be used bind to several other proteins simultaneously. Several natural proteins, such as haemoglobin, are composed of several protein sub-units hooked together and such quaternary structures have many unique and exciting possibilities for form and function, the properties of the sum being greater than those of each protein alone.

Related Links

Science 2016, online: "Design of structurally distinct proteins using strategies inspired by evolution"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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