Issue 168, April 2015 www.proteinspotlight.org Issue 168 Protein.Spotlight e838 a question of perspective Vivienne Baillie Gerritsen Paradigms are meant to be broken. In the 1980s, biology students were taught “the one gene = one protein” dogma which has since stepped down from its pedestal, as we now know that one gene, by way of any number of post-translational modifications on the protein sequence, can actually give rise to more than one protein. Or what would be more correct: to more than one function. In the same way, structural biologists are beginning to realise that proteins are not always stable bu t that a significant amount exist in particularly unstable forms – which has given them the name “disordered proteins”. Until recently, proteins were thought to fold up into thermodynamically stable forms before getting on with what they had to do. Now we know that it is not necessarily the case. Eukaryotic translation initiation factor 4E- binding protein 2, for instance, is one such disordered protein whose lack of stability gives rise to a new kind of biological regulation. But it took a further 20 years for such a notion to become popular. This is because of the angle from which structural biologists have been observing proteins. It is not an easy task to predict the kinetics and thermodynamics underlying the conformational states of a protein – not to mention those driving its catalytic reactions and binding properties. So, as is the case in scientific research, biologists set a basis from which they can make powerful correlations. In this case, low energy states and a limited number of combinations of macromolecules which provided links between the 3D conformation of proteins and by Jodee Knowles their functions. However, it is becoming Courtesy of the artist increasingly apparent that proteins carry out their business at higher energy states. Which is beginning to push the initial dogma over the cliff. Strangely enough, until the early 1950s, scientists believed that proteins were particularly malleable This just goes to show how paradigms – though entities. Then along came the pioneering work on necessary – can impede scientific progress by the necessity for two fragments of a ribonuclease to keeping the understanding of some phenomena bind tightly for it to be effective, and scientists within certain limits until other parameters, which began to produce the first crystal structures of researchers cannot ignore anymore, emerge and the proteins. Ever since, a stable 3D conformation was paradigm is interrupted and takes a jump forward. considered to be the ideal state for a protein to The low energy paradigm gave huge insight – and function. However, in 1986 already, a handful of over a long period – into the biological function of scientists were beginning to realise that perhaps a proteins, but it slowed the understanding, or few proteins carried out their existence a little acceptance, of highly dynamic states. differently, and were somewhat unsure as to the stable conformation they wished to adopt. So didn’t Proteins that lead a life in highly dynamic states are really adopt any at all. what has been coined “intrinsically disordered”, because they do not adopt one sole three- dimensional conformation and stick to it, but rather page 1 of 2 (not for indexing) e838 Issue 168 Protein.Spotlight they embrace a series of different conformations – binds to eIF4E very tightly and translation initiation although, from a purely thermodynamic point of is suppressed. view,they embracethey remain a series stable. of different Contrary conformations to expectations, – binds to eIF4E very tightly and translation initiation disorderedalthough, fromproteins a purely are notthermodynamic a rare event; point current of is suppressed.This is the first time researchers have discovered predictionsview, they remainestimate stable. that Contrary15% of tothe expectations, proteome is, that translation initiation can actually be regulated quote,disordered fully disordered!proteins are Hownot ado rare we event;know, currentyou may Thisvia is thethe structuralfirst time polymorphismresearchers have of discovered a protein, itself ask?predictions Thanks estimateto the fieldthat 15%of computational of the proteome biology is, thatmediated translation by initiation phosphorylation can actually – bea novelregulat edmode of andquote, algorithms fully disordered! that are ableHow to do predict we know, disorder… you may via biologicalthe structural modulationpolymorphism ofled a protein,by intrinsicallyitself ask? Thanks to the field of computational biology mediateddisordered by phosphorylation proteins. Disorder – a novel to order mode (andof vice Itand is algorithmshardly surprising that are able that to predict disordered disorder… proteins biologicalversa) involvesmodulation large conformationalled by intrinsically changes in a represent a significant challenge to structural disorderedprotein –proteins. as opposed Disorder to those to orderwhich (and occur vice when the biologists.It is hardly To surprisingcomplicate that matters disordered further proteins they are versa)more involves “common” large conformational ligands bind changes to their in a target notrepresent to be a consideredsignificant challengeonly at tothe structurallevel of proteinproteins – as opposedfor instance. to those EIF4EBP2 which occur is thewhen first the protei n biologists. To complicate matters further they are more “common” ligands bind to their target monomers… Disordered proteins lack perhaps a to have been discovered which undergoes multiple not to be considered only at the level of proteins for instance. EIF4EBP2 is the first protein stablemonomers… tertiary Disorderedstructure but proteins they arelack able perhaps to carr a y to havephosphorylation been discovered bringing which undergoes about multiplean important outstable numerous tertiary biologicalstructure butfunctions, they are especially able to carr thosey phosphorylationconformational bringing change. about an important associatedout numerous with biological signalling, functions, transcription especially regulatio those n, conformational change. cellassociated division with and signalling, differentiation. transcription And, regulatio as for n,the Disordered proteins are shedding light on an entire morecell divisionpopular andstable differentiation. proteins, And,post-translational as for the Disorderednew domain proteins areof sheddingbiology light and on anconcomitantly entire modificationsmore popular (PTMs) stable ofproteins, disordered post-translational proteins are a newshattering domain a oflong-standing biology and dogma. concomitantly They are able to sourcemodifications of additional (PTMs) offunctions. disordered As proteins an example, are a shatteringcarry a outlong-standing multiple dogma. functions They areby able wayto of disorderedsource of proteinadditional Eukaryotic functions. translation As an example, initiatio n carryconformational out multiple plasticity, functions which by itselfway depends of on factordisordered 4E-binding protein protein Eukaryotic 2 (EIF4EBP2) translation isinitiatio involvedn conformationalthe proteins’ plasticity, state ofwhich phosphorylation. itself depends onWhat is infactor the 4E-bindingsuppression protein of cap-dependent2 (EIF4EBP2) is translationinvolved the more,proteins’ given state regions of phosphorylation. within a disordered What protein is are initiation,in the suppression which is ofbrought cap-dependent about bytranslation multiple more,– depending given regions on theirwithin conformation a disordered protein– able toare interact initiation, which is brought about by multiple – depending on their conformation – able to interact phosphorylation of EIF4EBP2. with different target proteins, thus lending the phosphorylation of EIF4EBP2. with different target proteins, thus lending the proteinprotein multispecificity. multispecificity. Biologists Biologists are alsoare also EIF4EBP2EIF4EBP2 isis thethe major neuralneural isoform isoform of of a afamily family beginningbeginning to realiseto realise that disorderedthat disordered proteins proteins are are ofof proteins proteins that that bindbind to aa translationtranslation initiation initiation factor factor probablyprobably at the at heartthe heart of evolution of evolution since theysince offer they offer eIF4EeIF4E – – so so longlong as another initiationinitiation factor factor known known rapidrapid regulatory regulatory complexity. complexity. This couldThis couldexplain explain the the asas eIF4GeIF4G hasn’thasn’t got therethere first!first! BindingBinding or or not not preponderancepreponderance of disordered of disordered proteins proteins in signalling in signalling bindingbinding toto eIF4EeIF4E all hashas toto dodo withwith thethe networksnetworks within within higher higher eukaryotes, eukaryotes, and scientists and scientists conformationconformation ofof EIF4EBP2 whichwhich depends depends on on its its expectexpect them them to be to involved be involved in various in various pathologies, pathologies, phosphorylation;phosphorylation; phosphorylation cancan occuroccur at at especiallyespecially those those characterized characterized by loss by of loss biologica of biological l multiplemultiple sites.sites. When EIF4EBP2EIF4EBP2 is is highlyhighly reactionreaction such such as cancer. as cancer. There There is still is much still tomuch learn to learn phosphorylated,phosphorylated, it is unable toto interact interact with with eIF4E eIF4E, , aboutabout disordered