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A new kind of periodic table
CAMBRIDGE, U.K.—The Periodic Table of Protein Complexes, published in Science, is expected to offer a new way of looking at the enormous variety of structures that proteins can build in nature, understanding which ones might be discovered next and predicting how entirely novel structures could be engineered. Created by an interdisciplinary team led by researchers at the Wellcome Trust Genome Campus and the University of Cambridge, the table provides, they say, a valuable tool for research into evolution and protein engineering.
Almost every biological process depends on proteins interacting and assembling into complexes in a specific way, and many diseases are associated with problems in complex assembly. The principles underpinning this organization are not yet fully understood, but by defining the fundamental steps in the evolution of protein complexes, the new “periodic table” presents a systematic, ordered view on protein assembly, providing a visual tool for understanding biological function.
“We’re bringing a lot of order into the messy world of protein complexes,” according to Sebastian Ahnert of the Cavendish Laboratory at the University of Cambridge, a physicist who regularly tangles with biological problems. “Proteins can keep going through several iterations of these simple steps, adding more and more levels of complexity and resulting in a huge variety of structures. What we’ve made is a classification based on these underlying principles that helps people get a handle on the complexity.”
“Evolution has given rise to a huge variety of protein complexes, and it can seem a bit chaotic,” explains Joe Marsh, formerly of the Wellcome Genome Campus and now of the MRC Human Genetics Unit at the University of Edinburgh. “But if you break down the steps proteins take to become complexes, there are some basic rules that can explain almost all of the assemblies people have observed so far.”
Different ballroom dances can be seen as an endless combination of a small number of basic steps. Similarly, the “dance” of protein complex assembly can be seen as endless variations on dimerization (one doubles, and becomes two), cyclization (one forms a ring of three or more) and subunit addition (two different proteins bind to each other). Because these happen in a fairly predictable way, it’s not as hard as you might think to predict how a novel protein would form, the researchers say. And the exceptions to the rule are interesting in their own right, adds Ahnert, and are the subjects of their own ongoing studies.
“By analyzing the tens of thousands of protein complexes for which three-dimensional structures have already been experimentally determined, we could see repeating patterns in the assembly transitions that occur—and with new data from mass spectrometry, we could start to see the bigger picture,” says Marsh.
The Periodic Table of Protein Complexes will be a helpful tool for students and researchers.
“It’s useful for classifying protein complexes,” Marsh informs DDNews. “People have used tools like SCOP and CATH to classify protein tertiary structure for many years, but there hasn't been much in the way of classifying quaternary structure, so this table provides a simple way to do that. It can also help you predict the likely quaternary structure of a complex, provided you already know something about its subunit composition.”
“The core work for this study is in theoretical physics and computational biology, but it couldn’t have been done without the mass spectrometry work by our colleagues at Oxford University,” adds Sarah Teichmann, Research Group Leader at the European Bioinformatics Institute of the European Molecular Biology Laboratory (EMBL-EBI) and the Wellcome Trust Sanger Institute. “This is yet another excellent example of how extremely valuable interdisciplinary research can be.”
“The data in this study is based upon nano-electrospray mass spectrometry measurements, which have the feature of being able to preserve non-covalent interactions in the gas phase, thus giving a nice way to identify all the different subcomplexes that form during assembly and disassembly. By looking at these mass spec measurements for many complexes, we could identify what types of assembly transitions are most common,” Marsh tells DDNews.
According to Marsh, researchers are still very interested in trying to understand the evolutionary pathways of protein complexes, in particular heteromeric complexes. “We are currently doing some work on how the assembly pathways of heteromers are related to their evolution. Now that I've started my own research group in Edinburgh, one of my main focuses is on understanding how pathogenic mutations can disrupt the assembly of protein complexes, and how protein complex assembly and quaternary structure can influence the phenotypic impacts of mutations.”
An interactive version of this table with information on the structures represented by each topology can be found at www.periodicproteincomplexes.org.