Field of Science

Promiscuous proteins

Gone are the days when the one protein, one function presumption prevailed. Many proteins are multifunctional and multispecific, that is they have multiple binding partners for carrying out various roles in the cell. Here's a new review by Erijiman et al. in Biochemistry about multispecifity, covering various examples of promiscuous proteins and the different ways in which they achieve their multispecificity.

Proteins can interact with multiple binding partners by having distinct binding interfaces or domains. By this route, it's possible for the protein to optimise each binding site for its specific partner as the interfaces are independent (although there may be some cross-talk). An example of this from the proteins that I'm interested in is the Rel protein of bacteria. This protein has a synthesis domain for producing the alarmone ppGpp, and a hydrolysis domain for degrading it. The interfaces are on different sides of the protein, so are in some sense independent, although binding of a molecule in one site may influence the function of the other site by switching the conformation of the protein.

As an alternative solution, a protein may bind through one interface that is able to interact with multiple partners. An example of this is the archaeal elongation factor EF1A, which delivers aminoacylated tRNA, release factor aRF1 and mRNA decay protein aDom34 to the ribosome, binding all three by overlapping binding sites.

My rather simplistic representation of how a protein's binding interfaces can be distributed. A: independent binding sites eg Rel. B: overlapping binding sites eg aEF1A.

Multispecificity is great for the cell (especially cells with reduced, streamlined genomes) in that from just one gene, you get a lot of functional value. However, it also introduces some compromises for the protein, in terms of optimising its specificity for binding partners (especially true for proteins with overlapping binding sites), and brings about challenges in terms of regulating the different functions. A way to escape these problems is by gene duplication and subfunctionalisation for the different binding functions of the protein. Indeed this has occurred in some organisms for both of my examples above. In proteobacteria, Rel has been duplicated, resulting in RelA and SpoT, specialised for ppGpp synthesis and hydrolysis respectively. Similarly, in eukaryotes, two duplications of EF1A-like proteins have led to eEF1A, eRF3 and Hbs1, specialised for binding aa-tRNA, eRF1 and eDom34 respectively. However, it would be wrong to say that eEF1A now only has one function, as in fact it has many many more functions... but that's another story!

For more info on these proteins, check out my other blog posts:

Erijman A, Aizner Y, & Shifman JM (2011). Multispecific recognition: mechanism, evolution, and design. Biochemistry, 50 (5), 602-11 PMID: 21229991

Hogg T, Mechold U, Malke H, Cashel M, & Hilgenfeld R (2004). Conformational antagonism between opposing active sites in a bifunctional RelA/SpoT homolog modulates (p)ppGpp metabolism during the stringent response [corrected]. Cell, 117 (1), 57-68 PMID: 15066282

Saito K, Kobayashi K, Wada M, Kikuno I, Takusagawa A, Mochizuki M, Uchiumi T, Ishitani R, Nureki O, & Ito K (2010). Omnipotent role of archaeal elongation factor 1 alpha (EF1α in translational elongation and termination, and quality control of protein synthesis. Proceedings of the National Academy of Sciences of the United States of America, 107 (45), 19242-7 PMID: 20974926

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Markup Key:
- <b>bold</b> = bold
- <i>italic</i> = italic
- <a href="">FoS</a> = FoS