The power of two: protein dimerization in biology

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The self-association of proteins to form dimers and higher-order oligomers is a very common phenomenon. Recent structural and biophysical studies show that protein dimerization or oligomerization is a key factor in the regulation of proteins such as enzymes, ion channels, receptors and transcription factors. In addition, self-association can help to minimize genome size, while maintaining the advantages of modular complex formation. Oligomerization, however, can also have deleterious consequences when nonnative oligomers associated with pathogenic states are generated. Specific protein dimerization is integral to biological function, structure and control, and must be under substantial selection pressure to be maintained with such frequency throughout biology.

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Dimerization regulates function

One of the problems that we face in trying to understand the role of protein dimerization in biology is the relative paucity of biophysical data: in comparison to the numbers of known proteins, few polypeptides are well characterized in terms of their oligomerization state. Enzymes form a general class of proteins that has been probably characterized the best. A search of the Brenda enzyme database (http://www.brenda.uni-koeln.de/) shows that, out of a total of 452 human enzymes for which the

Partners in providing transport across membranes

The oligomerization and activation of cell-surface receptors in response to the binding of an agonist is a common theme in the pathways that transfer a signal across the cell membrane; for example, growth hormone, interferon, cytokine and tyrosine kinase receptor families all use this approach [8]. G-protein-coupled receptors (GPCRs), the most common class of cell-surface receptors, were traditionally thought to function as monomers; however, the recent observation of cooperativity in

DNA binding and gene expression

Many DNA-binding proteins that are involved in diverse processes, such as DNA repair, DNA replication and gene expression, form dimers or higher-order oligomers. Some of the most elegant examples of the role of protein dimerization in DNA binding can be found in orthodox type II restriction enzymes. These proteins, which are present in most bacteria and are essential to recombinant DNA technologies, bind to palindromic DNA sequences [22]. Each subunit of the homodimer contacts one-half of the

Dimers, oligomers and the economy of scale

The oligomerization of multiple, identical subunits provides a relatively simple and economical way for organisms to form large structures. These structures might be very stable, such as the long fibrous extracellular matrix proteins myosin and collagen that can last a human lifetime. Others might be much more dynamic; for example, tubulin heterodimers (composed of α and β subunits) can be added or removed from either end of microtubules in a GTP-dependent fashion [30] to form the structural

Native and pathogenic oligomerization interfaces

Although geometric analysis of interaction sites has shown that the interfaces of both heterocomplexes and homocomplexes are generally circular and planar 40, 43, there are other specific modes of dimerization such as metal binding and domain swapping. The zinc hook motif, which is present in the DNA repair complex protein RAD50, is formed when two cysteine residues from each monomer unit coordinate a single Zn2+ ion in a tetrahedral manner [44] (Figure 2e). Three-dimensional domain-swapped

Concluding remarks

Protein dimerization or oligomerization is a common physical property of proteins and represents a constantly recurring theme in biological systems. Dimers and oligomers contribute to numerous cellular processes. They provide stability, increase enzyme activity by concentrating the active site, facilitate a rise in the local concentration of molecules, transmit signals, and channel reagents (small molecules and ions) across membranes. Dimerization and oligomerization expand the opportunities

Acknowledgements

We thank D. Gell, N. Hoogenraad, and J. Mackay for critical comments on the article; and H.B.F. Dixon, E. Teber and B. Church for useful discussions. J.M.M. is supported by the Sylvia and Charles Viertel Foundation.

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