Tompa / Fersht Structure and Function of Intrinsically Disordered Proteins

1. Auflage 2010
ISBN: 978-1-4200-7893-0
Verlag: Taylor & Francis
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 359 Seiten

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.

Zielgruppe

Biophysicists, protein scientists, molecular biologists, biochemists, and bioinformaticians; advanced undergraduate and graduate students in biology, chemistry, and physics; pharmaceutical researchers.

Autoren/Hrsg.

Tompa, Peter

Fersht, Alan

Fachgebiete

• Naturwissenschaften Biowissenschaften Proteinforschung

Inhaltsverzeichnis

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
References

Über Autor(innen)

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.