- Email: [email protected]
Conclusion and future directions
CHAPTER
Conclusion and future directions
10 Nicola Salvi1
Institut de Biologie Structurale (IBS), CEA, CNRS, University Grenoble Alpes, Grenoble, France 1 Corresponding author. E-mail: [email protected]
There is a fundamental relationship between protein dynamics and function: similar to human-made machinery, motions are required for biomolecules to exert their biological function. This basic fact was accepted long ago by the scientific community in the case of folded proteins. For example, folded enzymes usually populate a number of well-defined conformational states, and what defines whether an enzyme is active and its kinetics is often such conformational dynamics. In other words, it is very tempting to try to interpret biology in terms of structure-function relationships, but there is definitely more than meets the eye. This is even more true in the case of intrinsically disordered proteins and regions where the very concept of “structure” becomes elusive, as IDPs and IDRs populate a continuum of conformations, as we discussed in Chapters 1 and 2. Actually, the idea of continuum underlies the entire book. Having to deal with a continuum of conformers, as opposed to one or several well-defined conformational states, is a challenge for the experimental characterization of IDPs and IDRs. The past 15 years witnessed the development of a variety of experimental techniques to probe disordered proteins. In Chapters 3 and 4, we discussed how nuclear magnetic resonance and single-molecule fluorescence are used to describe the structural features of IDPs but also the dynamics of interconversion between distinct conformers, which occur on multiple time scales from picoseconds to hours. This experimental evidence, together with computational modeling (Chapter 6), is precious for the identification of the molecular mechanisms by which IDPs and IDRs exert their function by binding to their functional partner(s), as discussed in Chapter 5. We have seen that IDP binding features a number of continuously distributed properties: IDPs can remain disordered in complex with other proteins or fold into rigid structures; binding energies display a continuous distribution that include both very weak and very strong interactions; finally, binding can result in 1:1 complexes but also multivalent oligomers in which the stoichiometry of the system is somewhat less well defined. In summary, IDPs and IDRs have unique biophysical properties that provide them with the capability of establishing interactions with low affinity and high specificity. Nature exploits this Intrinsically Disordered Proteins. https://doi.org/10.1016/B978-0-12-816348-1.00010-7 © 2019 Elsevier Inc. All rights reserved.
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CHAPTER 10 Conclusion and future directions
feature of disordered proteins in many ways and most notably in cellular functions, such as signaling, that require the quick assembly and disassembly of functional complexes. As more and more interactions are characterized, we think that in the near future the focus of the field of IDPs will shift from biophysical descriptions to applications in biology, chemistry, and medicine. In the last part of the book, we tried to identify three major directions that the field has taken more recently. For example, the recent recognition that many disordered proteins undergo liquid-liquid phase separation to form membraneless organelles (Chapter 7) is radically changing our understanding of many biological phenomena, including, for example, DNA replication. Disordered proteins and regions seem to be key elements in the formation of a continuum of intermolecular interactions that underlies the formation of a network of biomolecules, which holds together a protein-rich liquid phase. The combined efforts of computational and experimental scientists are progressively revealing the role played by disorder in phase separation. This is not only major intellectual progress in life science, but also an opportunity for the identification of new pharmaceutical targets, as aberrant production or posttranslational modification of proteins associated with membraneless organelles often results in pathological states. Sometimes, the formation of IDP aggregates leads to the formation of unsoluble fibrils that are the hallmark of many diseases, including Alzheimer and Parkinson diseases (Chapter 8). Research in this field is revealing that cytotoxicity is not only a property of large, unsoluble aggregates but also of a continuum of olygomers that allegedly disrupts cellular membranes by hitherto unknown mechanisms. Similar to membraneless organelles, the identification and structural and dynamic characterization of the toxic olygomers will activate new targets for drug development. Finally, a more general perspective on the use of IDPs and IDRs in drug discovery is given in Chapter 9. Of course, there are many future perspectives and applications that were not extensively discussed in this book. For example, we anticipate that IDPs could inspire the development of new biocompatible materials for a variety of purposes. This is actually already the case for phase-separating peptides that are being used for drug delivery and for assembling nanoreactors. In summary, the discovery of IDPs has radically changed our understanding of biology, and promises to provide us with new tools to solve biological, biotechnological, chemical, and pharmaceutical problems. We hope that the reader has found in our book the key concepts to interpret past and future progress in the field.
Acknowledgments The author acknowledges financial support from the Swiss National Science Foundation (Advanced Postdoc.Mobility Fellowship P300P2_167742).
Conclusion and future directions
10 Nicola Salvi1
Institut de Biologie Structurale (IBS), CEA, CNRS, University Grenoble Alpes, Grenoble, France 1 Corresponding author. E-mail: [email protected]
There is a fundamental relationship between protein dynamics and function: similar to human-made machinery, motions are required for biomolecules to exert their biological function. This basic fact was accepted long ago by the scientific community in the case of folded proteins. For example, folded enzymes usually populate a number of well-defined conformational states, and what defines whether an enzyme is active and its kinetics is often such conformational dynamics. In other words, it is very tempting to try to interpret biology in terms of structure-function relationships, but there is definitely more than meets the eye. This is even more true in the case of intrinsically disordered proteins and regions where the very concept of “structure” becomes elusive, as IDPs and IDRs populate a continuum of conformations, as we discussed in Chapters 1 and 2. Actually, the idea of continuum underlies the entire book. Having to deal with a continuum of conformers, as opposed to one or several well-defined conformational states, is a challenge for the experimental characterization of IDPs and IDRs. The past 15 years witnessed the development of a variety of experimental techniques to probe disordered proteins. In Chapters 3 and 4, we discussed how nuclear magnetic resonance and single-molecule fluorescence are used to describe the structural features of IDPs but also the dynamics of interconversion between distinct conformers, which occur on multiple time scales from picoseconds to hours. This experimental evidence, together with computational modeling (Chapter 6), is precious for the identification of the molecular mechanisms by which IDPs and IDRs exert their function by binding to their functional partner(s), as discussed in Chapter 5. We have seen that IDP binding features a number of continuously distributed properties: IDPs can remain disordered in complex with other proteins or fold into rigid structures; binding energies display a continuous distribution that include both very weak and very strong interactions; finally, binding can result in 1:1 complexes but also multivalent oligomers in which the stoichiometry of the system is somewhat less well defined. In summary, IDPs and IDRs have unique biophysical properties that provide them with the capability of establishing interactions with low affinity and high specificity. Nature exploits this Intrinsically Disordered Proteins. https://doi.org/10.1016/B978-0-12-816348-1.00010-7 © 2019 Elsevier Inc. All rights reserved.
329
330
CHAPTER 10 Conclusion and future directions
feature of disordered proteins in many ways and most notably in cellular functions, such as signaling, that require the quick assembly and disassembly of functional complexes. As more and more interactions are characterized, we think that in the near future the focus of the field of IDPs will shift from biophysical descriptions to applications in biology, chemistry, and medicine. In the last part of the book, we tried to identify three major directions that the field has taken more recently. For example, the recent recognition that many disordered proteins undergo liquid-liquid phase separation to form membraneless organelles (Chapter 7) is radically changing our understanding of many biological phenomena, including, for example, DNA replication. Disordered proteins and regions seem to be key elements in the formation of a continuum of intermolecular interactions that underlies the formation of a network of biomolecules, which holds together a protein-rich liquid phase. The combined efforts of computational and experimental scientists are progressively revealing the role played by disorder in phase separation. This is not only major intellectual progress in life science, but also an opportunity for the identification of new pharmaceutical targets, as aberrant production or posttranslational modification of proteins associated with membraneless organelles often results in pathological states. Sometimes, the formation of IDP aggregates leads to the formation of unsoluble fibrils that are the hallmark of many diseases, including Alzheimer and Parkinson diseases (Chapter 8). Research in this field is revealing that cytotoxicity is not only a property of large, unsoluble aggregates but also of a continuum of olygomers that allegedly disrupts cellular membranes by hitherto unknown mechanisms. Similar to membraneless organelles, the identification and structural and dynamic characterization of the toxic olygomers will activate new targets for drug development. Finally, a more general perspective on the use of IDPs and IDRs in drug discovery is given in Chapter 9. Of course, there are many future perspectives and applications that were not extensively discussed in this book. For example, we anticipate that IDPs could inspire the development of new biocompatible materials for a variety of purposes. This is actually already the case for phase-separating peptides that are being used for drug delivery and for assembling nanoreactors. In summary, the discovery of IDPs has radically changed our understanding of biology, and promises to provide us with new tools to solve biological, biotechnological, chemical, and pharmaceutical problems. We hope that the reader has found in our book the key concepts to interpret past and future progress in the field.
Acknowledgments The author acknowledges financial support from the Swiss National Science Foundation (Advanced Postdoc.Mobility Fellowship P300P2_167742).