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Much like Legos, proteins can come together in a number of ways to create complex structures. The various ways make it hard to organize protein complexes into categories.
But now, in a paper just out in Science, researchers describe an approach to classify protein complexes that creates a periodic table, like the periodic table that’s used in chemistry to organize elements. “We're bringing a lot of order into the messy world of protein complexes," says Sebastian Ahnert at the University of Cambridge. Ahnert is the first author on the paper.
The investigators say that the fact that almost all known protein complexes could be arranged into a periodic table is revealing and will help understand how protein complexes come about. “Most heteromeric protein complexes—ones with more than one protein type—consist of identical repeated units of several protein types,” says Ahnert. “Because of this, heteromeric protein complexes can, in fact, be viewed as simpler, homomeric protein complexes—ones that only consist of a single type of protein—if we think of these repeated units as larger 'single proteins.’”
We first examined the fundamental steps by which protein complexes can assemble, using electrospray mass spectrometry experiments, literature-curated assembly data, and a large-scale analysis of protein complex structures. We found that most assembly steps can be classified into three basic types: dimerization, cyclization, and heteromeric subunit addition. By systematically combining different assembly steps in different ways, we were able to enumerate a large set of possible quaternary structure topologies, or patterns of key interfaces between the proteins within a complex. The vast majority of real protein complex structures lie within these topologies. This enables a natural organization of protein complexes into a “periodic table,” because each heteromer can be related to a simpler symmetric homomer topology.
Exceptions are mostly the result of quaternary structure assignment errors, or cases where sequence-identical subunits can have different interactions and thus introduce asymmetry. Many of these asymmetric complexes fit the paradigm of a periodic table when their assembly role is considered. Finally, we implemented a model based on the periodic table, which predicts the expected frequencies of each quaternary structure topology, including those not yet observed. Our model correctly predicts quaternary structure topologies of recent crystal and electron microscopy structures that are not included in our original data set.
This work explains much of the observed distribution of known protein complexes in quaternary structure space and provides a framework for understanding their evolution. In addition, it can contribute considerably to the prediction and modeling of quaternary structures by specifying which topologies are most likely to be adopted by a complex with a given stoichiometry, potentially providing constraints for multi-subunit docking and hybrid methods. Lastly, it could help in the bioengineering of protein complexes by identifying which topologies are most likely to be stable, and thus which types of essential interfaces need to be engineered.