Protein disorder — a breakthrough invention of evolution?
Highlights
► Well-structured and disordered regions occupy different regions in the protein universe and both differ from random. ► It seems useful to see protein disorder as a unique aspect of protein structure rather than structural flexibility. ► Although the term protein disorder describes a variety of features, each shares the label disorder. ► Protein disorder is often surprisingly conserved in evolution and serves as its building block. ► We need better experimental and computational methods to handle protein disorder to better understand its role in biology.
Introduction
The once Central Dogma of Molecular Biology (‘DNA makes RNA makes protein’) has cracked due to the discovery of the functional importance of noncoding RNA [1]. The ‘Central Dogma of Genomics that derives from structural biology’ [2] implies that proteins adopt unique three-dimensional (3D) structures, and that the intricate detailed order in these 3D protein structures determines protein function. Over the last decade, experimental and computational structural biologists have been accumulating surprising evidence: Every organism seemingly has proteins that appear not to adopt 3D structures in isolation, that is, contains disorder. Is it time for the dog to eat the dogma [2] that sequence determines structure determines function, as Greg Petsko so poetically phrased it?
Since 3D details can determine function structures have evolved to exhibit innate and specific flexibility [3, 4, 5, 6]. Functional flexibility spans a wide range in terms of the time scale and the amount of motion [7]. Is protein disorder just an extreme example for flexibility, and if so: would this save the dogma a little longer?
Section snippets
Disorder is a mixed bag
Here, we refer to disordered regions as those regions in proteins that, when in isolation (i.e., not bound to other molecules), do not fold into a well-defined 3D structure but rather sample a large portion of their available conformational space. Put differently, if we could observe disordered regions in isolation at two different times, we would see two grossly different structures [8, 9, 10]. This definition covers local flexible loops, extended domains, molten globule domains, and folded
Eukaryotes more disordered than prokaryotes
In 1995, we got the first glimpse at an entirely sequenced organism [60], while others from all super-kingdoms of life have been following [61]. Several attempts have been made to find simple protein features that distinguish super-kingdoms [62, 63]. Surprisingly, eukaryotic and prokaryotic proteins resemble each other in terms of number of domains, protein length, and amino acid composition (with some caveats [63, 64, 65, 66]). In contrast to early hypotheses, the fraction of membrane proteins
Differences between organisms from different habitats are imprinted upon disorder
We can study the relation between evolution and disorder is by analyzing disorder in prokaryotes (many diverse organisms are sequenced, evolutionary relations can be quantified [76], and disorder predictions are accurate [77]). Our preliminary work suggests that differences between organisms from distinct habitats are imprinted upon the fraction of proteins with long disordered regions.
First, proteomes of thermophiles are well-structured, which might explain the high success rate of these for
Conclusions
In this perspective, we argue for three major views; none of those can be established, but we argue that accepting those for the time being is beneficial. Firstly, well-structured and disordered regions occupy different regions in the space of all sequences and both differ from random. Put differently, protein disorder is something new, not an extreme aspect of flexible regular structure. Secondly, although the term protein disorder describes a very mixed bag of features, the content of this
Acknowledgements
Thanks to Laszlo Kajan, Tim Karl, and Marlena Drabik (TUM), Julian Gough (Univ. Bristol) and Keith Dunker (Indiana Univ.), and Joel Sussman (Weizmann) for their important support; to the anonymous reviewer for improving this paper. Our work was supported by the Alexander von Humboldt Foundation, the TUM Institute for Advanced Study, funded by the German Excellence, and the following NIH grants: R01-LM07329, U54-GM75026-01, NIH F32-GM088991. Last, not least, thanks to all those who deposit their
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