The Three Functional States of Proteins

Structured, Intrinsically Disordered, and Phase Separated

1st Edition - November 17, 2024
Imprint: Academic Press
Editors: Timir Tripathi, Vladimir N Uversky
Language: English
Paperback ISBN:
9 7 8 - 0 - 4 4 3 - 2 1 8 0 9 - 5
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 2 1 8 1 0 - 1

The Three Functional States of Proteins explores how structured proteins, intrinsically disordered proteins, and phase separated proteins contribute to the complexity of ce… Read more

Purchase options

World Book Day Celebration!

Save up to 30% on books and eBooks!

Shop now

Institutional subscription on ScienceDirect

Request a sales quote

The Three Functional States of Proteins explores how structured proteins, intrinsically disordered proteins, and phase separated proteins contribute to the complexity of cellular life, and offers insights into their roles in both health and disease. It discusses the latest research findings and highlight groundbreaking discoveries and innovative methodologies used to study these protein states.
Traditionally, the different states of proteins have been defined based on their structures and functions. However, it is becoming increasingly clear that these criteria alone may not be sufficient to capture the complex and multifaceted properties of these molecules. Definitions based on thermodynamics and kinetics are now recognized as potentially more appropriate for comprehensively understanding protein states. Emerging evidence indicates that under physiological conditions, a majority of proteins possess the capability to exist in and transition between the native, droplet, and amyloid states. These distinct states play crucial roles in various cellular functions, influenced significantly by their physicochemical and structural properties. The book also considers the interactions among these states and discusses how their internal organization as individual molecules, as well as their collective organization as molecular assemblies are stabilized. Furthermore, it examines the processes by which these states are formed and the cellular functions associated with each specific state.

Title of Book
Cover image
Title page
Table of Contents
Copyright
List of contributors
Preface
Chapter 1. The three functional states of proteins: beyond the classical “lock and key” paradigm
Abstract
1.1 Structure-function continuum at the ground level: linking functional order and disorder
1.2 Functionality in 1D: functional amyloids
1.3 Protein quinary structure: membrane-less organelles and biomolecular condensates
References
Chapter 2. Ordered proteins and structure–function relationship: a classical view
Abstract
2.1 Protein structure: classical view
2.2 Tools and techniques which fashioned the classical enzymology
2.3 Chemical modification, chemical cross-linking, bioconjugation
2.4 RNase A and RNase S as evergreen models for exploring structure–function relationships
2.5 Conclusions
References
Chapter 3. Binding of a substrate (“lock and key”) and conformational adaption (“induced fit”) are different stages of enzyme action
Abstract
3.1 Introduction
3.2 The concept of “native structure” and its evolution
3.3 Protein dynamics: moving away from the “rigid lock” concept
3.4 Induced fit: a legacy of Emil-Fischer’s ideas
3.5 Enzymes/proteins, which conform to the induced fit mechanism
3.6 “Conformational selection” model: not quite like looking for “a needle in a haystack”
3.7 Distinguishing between the “induced folding” and “conformational selection” mechanisms
3.8 What model is followed by intrinsically disordered proteins/intrinsically disordered regions?
3.9 Conclusions
References
Chapter 4. Intrinsically disordered proteins: functionality of chaos
Abstract
4.1 Introduction
4.2 Types of IDPs
4.3 Mechanisms of IDP function
4.4 Biological importance of IDPs
4.5 Methods to study IDPs
4.6 Conclusion
Acknowledgment
References
Chapter 5. Protein conformation-based phenotypic switching and implications in the origin and evolution of multicellularity
Abstract
5.1 Introduction
5.2 Correlation between protein disorder and biological complexity
5.3 Noise and phenotypic switching
5.4 IDPs, prion-like IDPs, and protein conformation-based phenotypic switching
5.5 Stochastic mathematical models to delve into the dynamics of multicellularity
5.6 Conclusions and future directions
Conflict of Interest
References
Chapter 6. Hybrid proteins: fusion chimeras and natural wonders
Abstract
6.1 Introduction
6.2 Chimeric proteins generated by gene translocation
6.3 Grafting of functional peptides
6.4 Structure–function relationship of hybrid proteins
6.5 Exploring the functional significance of hybrid proteins
6.6 Hybrid proteins, containing ordered and disordered regions
6.7 Methods used to study hybrid proteins
6.8 Examples and case studies of hybrid proteins
6.9 Conclusion and future directions
References
Chapter 7. Functional protein oligomers
Abstract
7.1 Introduction
7.2 Types of protein oligomers
7.3 Symmetry and asymmetry in protein oligomers
7.4 Types of functional oligomers
7.5 Role of intrinsic disorder in oligomer formation
7.6 Regulation of protein oligomers
7.7 Protein oligomers in health and disease
7.8 Conclusion
Acknowledgments
References
Chapter 8. Fuzzy complexes
Abstract
8.1 Introduction
8.2 Classification
8.3 Biological functions
8.4 Pathology and druggability
8.5 Experimental and computational characterization
8.6 Conclusion
Acknowledgments
References
Chapter 9. SMARTQ: single-molecule amyloid fibRil tracking and quantification. A method for accurately imaging, tracking, and quantifying the growth of individual amyloid fibrils using TIRF
Abstract
9.1 Introduction
9.2 The SMARTQ procedure
9.3 Conclusion
Acknowledgments
Abbreviations
References
Chapter 10. Structural polymorphism in amyloids—states within proteins’ solid-state
Abstract
10.1 Biochemistry and biophysics of protein aggregation and amyloid formation
10.2 Polymorphism and phenotypes
10.3 Origins of polymorphic amyloid fibrils
10.4 Aβ
10.5 Tau
10.6 α-Synuclein
10.7 TDP-43
10.8 Polymorphism via heterotypic protein–protein interaction—a new frontier in amyloid polymorphism
10.9 Conclusions
References
Chapter 11. Liquid–liquid phase separation, biomolecular condensates, and membraneless organelles: a novel blueprint of intracellular organization
Abstract
11.1 Introduction
11.2 Liquid–liquid phase separation in biomolecular condensates
11.3 Interactions in LLPS, biomolecular condensates, and MLOs
11.4 Regulation of formation of biomolecular condensates
11.5 Roles of biomolecular condensates and MLOs in diseases
11.6 LLPS, biomolecular condensates, and MLOs: opportunities for drug discovery and therapeutic interventions
11.7 Imaging and visualization techniques for studying LLPS, biomolecular condensates, and MLOs
11.8 Challenges in studying LLPS, biomolecular condensates, and MLOs
11.9 Future prospects and implications
11.10 Conclusions
References
Chapter 12. Physical principles and molecular interactions underlying protein phase separation
Abstract
12.1 Introduction to protein phase separation
12.2 Thermodynamics and driving forces of protein phase separation
12.3 Molecular interactions in protein phase separation
12.4 Regulation of phase separation
12.5 Functional implications of protein phase separation
12.6 Targeting protein phase separation for drug discovery
12.7 Conclusion and future directions
References
Chapter 13. Various levels of phase transitions in the protein universe and around
Abstract
13.1 Introduction
13.2 Phases and phase transitions
13.3 Intramolecular phase transitions in disordered proteins induced by interactions with binding partners
13.4 Proteins that catalyze and inhibit phase transitions: ice nucleation and antinucleation
13.5 Protein amorphous aggregation, fibrillation, and crystallization as intermolecular phase transitions
13.6 Reincarnation of liquid–liquid and liquid–gel phase transitions: drivers of the biogenesis of membrane-less organelles and biomolecular condensates
13.7 Conclusions
Acknowledgments
Author Contributions
Funding
Conflict of Interest
References
Chapter 14. Targeting phase separated protein states for drug discovery
Abstract
14.1 Introduction
14.2 Biophysics underlying protein phase separation
14.3 Diseases associated with protein phase separation
14.4 Strategies for targeting phase separated protein states for drug discovery
14.5 Targeting phase separated protein states for drug discovery
14.6 Future directions and emerging technologies to assist in targeting phase separated states for drug discovery
14.7 Conclusions and future prospects
References
Chapter 15. Protein hydrogels: structure, characteristics, and applications
Abstract
15.1 Introduction
15.2 Crosslinking strategies in hydrogel production
15.3 Categories of protein hydrogels
15.4 Applications of protein hydrogels
15.5 Challenges of protein hydrogel applications and future directions
15.6 Conclusions
References
Chapter 16. Interactions among the three protein states
Abstract
16.1 Theoretical background
16.2 High-resolution structure determination
16.3 Nuclear magnetic resonance
16.4 Hydrodynamic analysis
Acknowledgments
References
Chapter 17. Frustration and fuzziness in the three functional states of proteins
Abstract
17.1 Introduction
17.2 Energy landscape theory of protein folding
17.3 Evolutionary perspectives on frustration and fuzziness
17.4 Frustration and fuzziness in phase-separated protein assemblies
17.5 Experimental approaches to probing frustration and fuzziness in distinct functional states
17.6 Computational approaches to investigating fuzziness in different states
17.7 Conclusion
Acknowledgments
References
Chapter 18. Thermoresponsive intrinsically disordered protein polymers
Abstract
18.1 Introduction
18.2 Elastin-like polypeptides
18.3 Resilin-like polypeptides
18.4 Silk-elastin-like proteins
18.5 Glutamine-rich polypeptides (Q-rich polypeptides)
18.6 Collagen-like polypeptides
18.7 Analysis and characterization of TIDPPs
18.8 Thermally responsive disordered polymer segments: a solubilization strategy based on entropic flexibility
18.9 Future directions for TIDDPs research
18.10 Conclusions
References
Chapter 19. The evolution and exploration of intrinsically disordered and phase-separated protein states
Abstract
19.1 What are intrinsically disordered regions?
19.2 IDRs across the tree of life
19.3 IDRs and the origin of proteins
19.4 Evolutionary selection of IDRs
19.5 Conserved sequence features of IDRs confer function
19.6 Phase separation as an emerging function of IDRs
19.7 Our knowledge of IDR evolution is limited to “alignable disorder”
19.8 Unalignable disorder—emerging methods to study IDR evolution
19.9 Conclusion and outlook
Acknowledgments
References
Chapter 20. Computational modeling of intrinsically disordered and phase-separated protein states
Abstract
20.1 Introduction
References
Chapter 21. Molecular dynamics simulations of intrinsically disordered proteins, fuzzy complexes, and phase-separated protein states
Abstract
21.1 Introduction
21.2 Insights into IDPs/IDRs from MD simulations
21.3 Insights into fuzzy complexes from MD simulations
21.4 Insights into phase-separation of proteins from MD simulation
21.5 Conclusions
Acknowledgments
References
Chapter 22. Biological complexity of the phase-separated protein states
Abstract
22.1 Introduction
22.2 Composition of biomolecular condensates: complexity of structural organization
22.3 Types of biomolecular condensates and related transitions
22.4 Characteristics of the biomolecular condensates: compartmentalization, localization, and regulation
22.5 Properties of phase-separated condensates
22.6 Peculiarities of the amino acid sequences of proteins engaged in phase separation
22.7 Structural and dynamic features of biomolecular condensates
22.8 Biomolecular condensates in diseases
22.9 Conclusions
Authors contributions
References
Chapter 23. Protein structure–function continuum
Abstract
23.1 Structure–function continuum at the individual molecule level
23.2 Structure–function continuum and functional amyloids
23.3 Structure–function continuum and membrane-less organelles
23.4 Structure–function continuum and the interplay between the three functional states of proteins: intrinsic disorder as one ring to rule them all
References
Index

Timir Tripathi

Professor Timir Tripathi is a Professor of Molecular Biology, School of Life Sciences, North-Eastern Hill University, Shillong, India. Earlier, he served as the Regional Director of Indira Gandhi National Open University. His previous role was Senior Assistant Professor and Principal Investigator at the Department of Biochemistry, NEHU, Shillong. He holds a Ph.D. from Jawaharlal Nehru University, New Delhi. His primary research focus is studying the conformational dynamics, interaction, and stabilization of the complexes formed by intrinsically disordered neuropathological protein aggregates, their properties of liquid-liquid phase separation, interaction, and roles in nucleocytoplasmic transport in neurodegenerative diseases. Professor Tripathi is an Associate Fellow of the Indian National Science Academy, New Delhi, and an elected member of the National Academy of Sciences, India, the Royal Society of Chemistry, and the Royal Society of Biology, UK

Affiliations and expertise

Professor of Molecular Biology, School of Life Sciences, North-Eastern Hill University, Shillong, India

Vladimir N Uversky

Prof. Vladimir N. Uversky, PhD, DSc, FRSB, FRSC, F.A.I.M.B.E., Professor at the Department of Molecular Medicine, Morsani College of Medicine, University of South Florida (USF), is a pioneer in the field of protein intrinsic disorder. He has made a number of groundbreaking contributions in the field of protein folding, misfolding, and intrinsic disorder. He obtained his academic degrees from Moscow Institute of Physics and Technology (Ph.D., in 1991) and from the Institute of Experimental and Theoretical Biophysics, Russian Academy of Sciences (D.Sc., in 1998). He spent his early career working mostly on protein folding at the Institute of Protein Research and the Institute for Biological Instrumentation (Russia). In 1998, moved to the University of California Santa Cruz. In 2004, joined the Indiana University−Purdue University Indianapolis as a Senior Research Professor. Since 2010, Professor Uversky is with USF, where he works on various aspects of protein intrinsic disorder phenomenon and on analysis of protein folding and misfolding processes. Prof. Uversky has authored over 1250 scientific publications and edited several books and book series on protein structure, function, folding, misfolding, and intrinsic disorder. He is also serving as an editor in a number of scientific journals. He was a co-founder of the Intrinsically Disordered Proteins Subgroup at the Biophysical Society and the Intrinsically Disordered Proteins Gordon Research Conference. Prof. Uversky collaborated with more than 12,500 colleagues from more than 2,750 research organizations in 89 countries/territories.

Affiliations and expertise

Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health