Getting a fix on proteins

20 November 2014
Nigel and Tet

Proteins are the molecular building blocks of life. There’s still a lot to learn about them – and tools developed by SBS post-doctoral researcher Tet Woo Lee promise a new approach.

The new computer-based tools help researchers systematically analyse proteins and detect which parts are critical for organic processes as opposed to those that simply regulate their shape. Given that a protein can be hundreds of amino acids long, identifying the critical bits can be a time-consuming process.

Dr Lee, pictured on the left in this photo with Associate Professor Nigel Birch, says his system is based on well-known evolutionary principles. Important amino acids in a protein tend to be conserved, which means they remain unchanged, whatever the evolutionary time scale. Any alterations of these amino acids usually affect the viability of the protein, resulting in the host organism being eliminated by natural selection.

In contrast, less important amino acids don’t affect a host’s survival, and may alter over time as mutations accumulate.  Identifying conserved amino acids is commonly used by researchers to identify important amino acids in proteins – but these conserved amino acids fall into two camps: they are important for either the biochemical function of the protein or for maintaining its shape and structure.

Dr Lee’s software tools identify just the biochemically important amino acids. In the first stage, conserved amino acids in a protein of interest are identified by comparing the sequences of the protein from a range of species, such as from fish to humans.

In the second stage, these conserved amino acids are compared to those in similar proteins that have the same shape, but different biochemical functions. Any amino acids that are also conserved in similar proteins are likely to be important for maintaining protein shape. By eliminating the amino acids that are also conserved in similar proteins, the amino acids important for the biochemical function of the protein of interest can be identified.

Dr Lee worked with Honours student Annie Shu-Ping Yang in Associate Professor Birch’s laboratory, and collaborated with Professor Thomas Brittain. He says that the tools – they don’t have a collective name – give scientists a valuable new way to home in on the regions of most interest. “That’s what everyone is interested in, whether they are studying protein function or doing drug design.”

Dr Lee proved his methods by applying them to an enzyme inhibitor called neuroserpin. “Our software tools identified several regions in neuroserpin that were likely to be involved in its biochemical activity. When we experimentally altered these parts of neuroserpin, we were able to produce different versions of the neuroserpin molecule that still had the same overall shape as the original molecule but had changes in the level of enzyme inhibition.”

He adds, “These tools could also be applied to other proteins to identify functionally important regions. This information could be used in a number of ways. For example, it could help us engineer enzyme variants that have altered catalytic activity, which could be useful in industry. Alternatively, it could help us to design drugs that target proteins that are of medical interest, as such drugs are usually designed to bind to biochemically-important parts of the protein molecule.”

This research was supported an Auckland Medical Research Foundation Postdoctoral Fellowship awarded to Dr Lee, as well as grants from Health Research Council of New Zealand, the Royal Society of New Zealand Marsden Fund and the School of Biological Sciences. The research has been published in the journal Proteins: Structure, Function and Bioinformatics. The article contains a link to the tool’s source code.