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Instant insight: Sorting perturbed proteins
05 February 2009
Ruth Nussinov of the National Cancer Institute at Frederick, US, and colleagues put their case for a more organised way of looking at protein allostery
Allostery is a universal phenomenon: all dynamic proteins are potentially allosteric. Crucial in all cellular pathways, it comes about when a perturbation by a molecule called an effector alters a protein's shape and/or dynamics and leads to a functional change at the substrate binding site. Allosteric perturbation can arise due to small or large molecule binding; changes in pH, temperature, ionic strength, or concentration; or from covalent modifications such as sugar or phosphoryl group linking. Yet, despite how much we know about how allostery occurs, how signals initiating at a perturbation site transmit through a protein is still an open question.
In seven-helix receptor enzymes GDP replacement by GTP involves two allosteric steps
The number, breadth and functional roles of documented protein allostery cases are rising quickly, creating a need to arrange the information into a logical order. Sorting and classifying allosteric mechanisms in this way should be extremely useful in understanding and predicting how the signals are regulated and transmitted in proteins.
Classification assists us in making sense of observations. What are the differences between plants and animals; between mammals, birds, reptiles, fish, and amphibians; between classes of protein structures; drugs; types of interactions and chemical reactions? Sorting objects into distinct categories organises the information, revealing patterns and relationships, and so provides insight. While the importance of classification is clear, how to classify and into which categories is less obvious.
We have presented a unified view of allostery and the first classification framework for allostery mechanisms. Allostery is a vehicle through which function is exerted so the logical approach was to organise mechanisms from a cellular function standpoint. Our framework is based on six properties, including whether there is conformational change at the substrate site and whether the effector perturbation increases or decreases the affinity of the substrate (positive or negative cooperativity respectively).
To illustrate this with an example, consider a textbook mechanism: GDP (guanosine diphosphate) replacement by GTP (guanosine triphosphate) in seven-helix receptor enzymes (see figure). Here classification indicates that two different types of allosteric step are involved. In the first (top), an extracellular ligand binds at an allosteric site causing a conformational change at the GDP binding site (the substrate site) leading to GDP's release. In the second allosteric step (bottom), the empty GDP binding site becomes an allosteric site for GTP binding. GTP binding then causes a protein to dissociate from the system - a negative cooperativity step.
Eventually, a classification scheme along the lines we propose could allow a systematic compilation and organisation of available allostery cases. The aim is to provide a tool to help scientists place allosteric mechanisms in context, allowing a better comprehension of the signalling pathways they affect and how these pathways are regulated. Ultimately, scientists would be able to predict signalling at the molecular level; it should also be useful for allosteric drug design.
Read more in the opinion article 'Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms' in Molecular BioSystems.
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Link to journal article
Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms
Chung-Jung Tsai, Antonio del Sol and Ruth Nussinov, Mol. BioSyst., 2009, 5, 207
Also of interest
Coupling between global dynamics and signal transduction pathways: a mechanism of allostery for chaperonin GroEL
Chakra Chennubhotla, Zheng Yang and Ivet Bahar, Mol. BioSyst., 2008, 4, 287
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