Structure and Function of Intrinsically Disordered Proteins  book cover
1st Edition

Structure and Function of Intrinsically Disordered Proteins

ISBN 9781420078923
Published November 18, 2009 by Chapman and Hall/CRC
359 Pages 82 B/W Illustrations

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Book Description

The existence and functioning of intrinsically disordered proteins (IDPs) challenge the classical structure-function paradigm that equates function with a well-defined 3D structure. Uncovering the disordered complement of proteomes and understanding their functioning can extend the structure-function paradigm to herald new breakthroughs in drug development. Structure and Function of Intrinsically Disordered Proteins thoroughly covers the history up to the latest developments in this field.

After examining the principles of protein structure, the classical paradigm, and the history of structural disorder, the book focuses on physical techniques for the identification and characterization of IDPs. It discusses proteomic and bioinformatic approaches and shows how IDPs behave under crowding conditions in living cells. The next several chapters describe the structure, correlating biological processes, and molecular mechanisms of IDPs. The author also explores the evolutionary advancement of structural disorder in proteomes and possible ways of extending the structure-function paradigm to encompass both ordered and disordered states of proteins. He concludes with discussions on the involvement of IDPs in various diseases and how to establish rational drug design through detailed characterization of IDPs.

Although drug discovery rates have leveled off, new insight generated by the study of IDPs may offer fresh strategies for drug development. This work illustrates how these proteins defy the structure-function paradigm and play important regulatory and signaling roles.

Table of Contents

Principles of Protein Structure and Function

Physical Forces That Shape Protein Structure

Primary Structure: Amino Acid Sequence

Protein-Coding Genes

Post-Translational Modifications of Amino Acids

Hierarchical Description of Structure

Folding of a Protein

Unfolding of a Protein: Lessons from Polymer Theory

The Limits of Global Descriptions of the Unfolded State

Databases of Proteins and Protein Structures

DisProt: The Database of Disordered Proteins

The Classical Structure-Function Paradigm

A Brief History of Protein Disorder

Can We Define Disorder?

The History of Disorder

So We Have Disordered Proteins

Indirect Techniques for Recognizing and Characterizing Protein Disorder

Resistance to Heat

Resistance to Chemical Denaturation

Unusual SDS-PAGE Mobility

Enhanced Proteolytic Sensitivity

Limited Proteolysis and Local Structure

Differential Scanning Calorimetry

Isothermal Titration Calorimetry

Chemical Cross-Linking

H/D Exchange

Hydrodynamic Techniques

Gel Filtration (Size-Exclusion) Chromatography

Dynamic Light Scattering

Analytical Ultracentrifugation

Small-Angle X-Ray Scattering

Pulsed-Field Gradient NMR

Spectroscopic Techniques for Characterizing Disorder

X-Ray Crystallography

Fluorescence Spectroscopy

Fourier-Transform Infrared Resonance Spectroscopy

Circular Dichroism

Raman Optical Activity Spectroscopy

Electron Paramagnetic Resonance Spectroscopy

Electron Microscopy

Atomic Force Microscopy

Nuclear Magnetic Resonance

Basic Principles

Global Characterization by NMR

Sequence-Specific Structural Information

Special Applications

Proteomic Approaches for the Identification of IDPs

Expectations and Limitations of Proteomic Studies

2DE-MS Identification of Proteins in Extracts Enriched for Disorder

Native/Urea 2DE Provides Direct Information on Disorder

IDPs under Conditions Approaching In Vivo

Macromolecular Crowding in the Cell

In Vitro Approaches to Mimicking Crowding Conditions

The State of IDPs In Vivo

Physiological Half-Life of IDPs: No Signs of Rapid Degradation

Indirect Considerations Underscoring Disorder of IDPs In Vivo

Prediction of Disorder

General Points

Propensity-Based Predictors

Machine-Learning Algorithms

Prediction Based on Interresidue Contacts

Prediction of Short and Long Regions of Disorder Separately

Combination of Predictors: Meta-Servers

Prediction of Functional Motifs in IDPs

Comparison of the Accuracy of Predictors: The CASP Experiment

A Better Target Prioritization in Structural Genomics

Structure of IDPs

Primary Structure of Disordered Proteins

Secondary Structure of Disordered Proteins

Ambiguity in Structure

Tertiary Structure: Global Features of IDP Structures

Dynamics of IDP Structure: The Time-Course of Fluctuations within the Ensemble

A Readout of Structure: The Hydrate Layer of IDPs

Biological Processes Enriched in Disorder

Biological Functions Enriched with Disorder

Disorder in Transcription/Transcription Regulation

Disorder in Signaling Proteins

Nucleic Acid-Containing Organelles

Disorder in RNA-Binding Proteins: Transcription and RNA Folding

Cytoskeletal Proteins

Disorder in Stress Proteins

Disorder and Metal Binding

Disorder and Enzyme Activity

Is There a Link between the Pattern of Disorder and Function?

Molecular Functions of Disordered Proteins

Entropic Chain Functions

Display Site Functions

Chaperone Functions

Effector Functions

Scavenger Functions

Assembler Functions

Prion Functions

Evolution and Prevalence of Disorder

Phylogenetic Distribution of Disorder

Fast Evolution of IDPs by Point Mutations

Fast Evolution of IDPs by Repeat Expansion

Fast Evolution and Functionality of Disordered Proteins

Structural Variability and Evolvability of New Functions

Extension of the Structure-Function Paradigm

Functions That Stem Directly from the Disordered State

Recognition Functions: Recognition by Short Motifs

Disorder-to-Order Transition in Recognition: Mechanistic and Thermodynamic Aspects

Recognition Functions: Uncoupling Specificity from Binding Strength

Implications of Disorder for the Kinetics of Interactions

Adaptability and Moonlighting

Nested Interfaces

Disorder in the Bound State: Fuzziness

Processivity of Binding

Sequence Independence in Recognition

Ultrasensitivity of Recognition

Signal Propagation in the Structural Ensemble of IDPs

Disorder and Alternative Splicing

Molecular Mimicry by a Disordered Region

Entropy Transfer in Chaperone Action

Structural Disorder and Disease

Structural Disorder and Cancer

Structural Disorder in Proteins Involved in Cardiovascular Diseases, Diabetes, and Autoimmune Diseases

Structural Disorder and Neurodegenerative Diseases

Systemic Amyloidoses

Common Themes in Amyloid Formation

Does Structural Disorder Pose a Danger?

Disorder in Pathogenic Organisms

Rational Drug Design Based on Protein Disorder


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Peter Tompa is Group Leader in the Laboratory of Intrinsically Disordered Proteins, Institute of Enzymology, Biological Research Center at the Hungarian Academy of Sciences in Budapest.


"Tompa's masterly compendium on intrinsically disordered proteins arrives at just the right time to fill a conspicuous void on this important topic. His eminently readable book is broad enough to educate beginners but deep enough to inform experts."
—George Rose, Ph.D., Johns Hopkins University, Baltimore, Maryland, USA

"Peter Tompa’s fine comprehensive overview of this rapidly advancing field is of timely importance, both for its documentation and for emphasizing the importance of IDPs in biology and protein science. … This book demonstrates Tompa’s considerable command of the field, providing appropriate examples and ample details in every respect. Its coverage of the latest developments in the field is impressive, and the author manages to strike a good balance between detail and concept to lead the reader through this novel field."
—From the Foreword by Professor Sir Alan Fersht, University of Cambridge, UK

"The book is just superb—a thorough, comprehensive and lucid discussion of intrinsically disordered proteins."
—Joel L. Sussman, Weizmann Institute of Science, Rehovot, Israel