Intrinsically disordered proteins

Our understanding of protein function has been predominated by the view that proteins need to adopt a defined three dimensional structure to be able to carry out their function. Indeed, crystal structures of numerous proteins have been instrumental in establishing the structure–function paradigm. For example, the structures of numerous enzymes have highlighted the need for particular chemical groups to be positioned in spatial proximity in order to catalyse specific reactions.

While this concept is absolutely fundamental for a large number of proteins, research over the last decade has identified segments in proteins that do not adopt a specific three dimensional structure but are nevertheless important for function. This suggests that conformational flexibility and heterogeneity might be important for certain types of protein function. Such segments, usually referred to as intrinsically disordered regions (IDRs), may either fold upon binding to the right interaction partner, or may still remain disordered in a complex. While there was scepticism from many researchers about the existence and the functional relevance of IDRs, exciting developments over the last few years have unambiguously established the functional contribution of disordered segments. Importantly, IDRs are prominent in the proteomes of all studied organisms.

Given the general excitement in this relatively young field, I believe that it is timely to dedicate a special issue of Molecular BioSystems to highlight the recent advances, experimental and computational methods, as well as emerging concepts involving IDRs.

Some of the current challenges in the field are (i) to develop new experimental and computational approaches to characterise IDRs and to identify functional parts within such regions, (ii) to gain a more comprehensive understanding of the sequence features, structural properties, expression patterns, molecular networks and evolution of proteins containing disordered segments, and (iii) to understand fundamental principles involving IDRs, such as how they mediate molecular recognition, regulation, folding, allostery, mutational robustness, etc. Addressing these challenges will have a profound impact on our understanding of (a) how IDRs contribute to the functioning of organisms, (b) how mutations in such regions can cause disease, and (c) how the distinct physico-chemical properties of IDRs can be exploited for applications in various fields such as nanotechnology, material sciences and biotechnology.

I am delighted that the 41 papers published in this themed issue all aim to address these challenges either directly or indirectly. The papers cover a spectrum of scientific topics from a wide range of model organisms and report specific discoveries, as well as general principles that can be applicable to a number of other systems. More importantly, the ideas and results presented in this themed issue firmly establish the fact that in addition to structured regions, disordered regions are essential for protein function. For the remaining few sceptics, I am reminded of a quote:

“The difficulty lies not in the new ideas but in escaping from the old ones” – John Maynard Keynes, Cambridge, UK.

I hope that the findings, reviews and approaches presented in this issue of Molecular BioSystems will serve as an inspiration for many scientists involved or interested in this area of research and that you will enjoy reading the papers.

M. Madan Babu, PhD

Associate Editor, Molecular BioSystems, UK

Programme Leader, MRC Laboratory of Molecular Biology, Cambridge, UK

Director of Studies, Trinity College, Cambridge, UK

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