Intrinsically Disordered Proteins Studied by NMR Spectroscopy

428 Pages·2015·17.505 MB·English

by  Isabella C. Felli, Roberta Pierattelli (eds.)

Advances in Experimental Medicine
and Biology
Volume 870
Editorial Board:
IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel
ABEL LAJTHA, Nathan S. Kline Institute for Psychiatric Research, Orangeburg,
NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy
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Isabella C. Felli • Roberta Pierattelli
Editors
Intrinsically Disordered
Proteins Studied by NMR
Spectroscopy
1 3
Editors
Isabella C. Felli Roberta Pierattelli
CERM and Department of Chemistry CERM and Department of Chemistry
“Ugo Schiff ” University of Florence “Ugo Schiff ” University of Florence
Florence Florence
Italy Italy
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-319-20163-4 ISBN 978-3-319-20164-1 (eBook)
DOI 10.1007/978-3-319-20164-1
Library of Congress Control Number: 2015948151
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Preface
Ignored for a long time in high-resolution studies of proteins, intrinsic protein
disorder is now recognized as one of the key features for a large variety of cellular
functions, where structural flexibility presents a functional advantage in terms
of binding plasticity and promiscuity. The properties of intrinsically disordered
proteins (IDPs) and protein regions (IDPRs) are highly complementary to those
deriving from the presence of a unique and well-defined three-dimensional fold.
Structural order, well characterized through the vast number of protein 3D structures
present in the Protein Data Bank (www.pdb.org), leading to highly organized
protein machines with well-defined binding pockets, lies at the heart of structural
biology. However, the functional importance of conformational flexibility, and the
characterization of residual transient structure in these protein regions, has only
recently attracted the attention of the scientific community and has immediately
found widespread interest in molecular biology research.
The tendency of a protein to adopt a stable globular structure such as the
number of folds we find in the Protein Data Bank or to be highly flexible and
able to sample many different conformations, directly results from the amino acid
primary sequence. It is not so surprising that a wide range of properties is needed
for proteins to carry out a broad range of functions and the idea that a high extent of
dynamics and flexibility provides important functional features nowadays appears
quite obvious. Structural disorder is abundant in higher multi-cellular organisms, in
particular in regulatory protein regions that orchestrate dynamic cellular functions
relying on spatial and temporal malleability. As a consequence, IDPs and IDPRs
are overrepresented in key functions of higher eukaryotes, i.e. transcriptional and
translational regulation, intracellular signaling, protein homeostasis, inter-cellular
communication, cell-fate decisions, and many more.
In this frame nuclear magnetic resonance (NMR) spectroscopy is the unique
technique able to provide high resolution information. However the peculiar
properties of IDPs do influence the NMR observables raising also several critical
questions that should be considered in the design of optimal NMR experiments
and in the interpretation of the data in terms of protein’s structural and dynamic
properties.
v
vi Preface
Recent progress in the field has radically changed our perspective to study
IDPs through NMR: increasingly complex IDPs can now be characterized, a wide
range of observables can be determined reporting on their structural and dynamic
properties, computational methods to describe the structure and dynamics are in
continuous development and IDPs can be studied in environments as complex as
whole cells.
Therefore we felt timely to convey these exciting recent developments in a book
and to do this in close interactions with pioneers in the field of IDPs as well as
with newcomers able to bring fresh energy and enthusiasm. We hope to be able to
communicate the new exciting possibilities offered by NMR and to present open
questions to foster further developments.
After an introductory chapter by Dunker and Oldfield describing the key steps
opening the field of IDPs, the book focuses on the many aspects that make NMR
a unique technique to study IDPs (Chaps. 2–5). Contributions discuss different
aspects starting from the first principles of NMR spectroscopy, including hardware
requirements, to the design and application of complex NMR experiments, to data
interpretation in terms of structural and dynamic properties, to the best ways to
achieve snapshots of IDPs in cells. Key to NMR analysis of complex proteins is
the possibility to have efficient heterologous protein expression, enabling stable
isotope incorporation. The tricks useful for IDPs samples preparation are reported
in Chap. 6.
Information at atomic resolution derived from NMR needs to be complemented
by information achieved through a variety of different biophysical methods reporting
on different properties of IDPs, as discussed in Chaps. 7–8. The use of predictors,
which may represent a preliminary step for any investigation, is reported in Chap. 9
while the perspectives for in-cell NMR in this field of research are discussed in
Chap. 10. Several examples of recent investigations and open questions are reported
in the final part of the book (Chaps. 12–14).
A separated chapter (Chap. 11) is dedicated to the PED, the database that has
been designed to deposit experimental data and calculate structural ensembles in
order to render these data feely accessible to the scientific community and stimulate
discussion and progress in the field.
With this book we hope to provide a useful guide to students and post-docs
approaching the field and willing to contribute to the characterization of IDPs
through NMR. Recent progress in NMR instrumentation, combined with the
development of new methods, has radically changed the perspective of the kind
of molecules we can study, the amount of information that we can achieve as well
as the time needed to complete an NMR characterization. Therefore we hope that
the new NMR tools developed will be increasingly used and contribute a wealth of
experimental information on IDPs. Speculating on more long-term perspectives,
the development of improved NMR methods to study IDPs is expected to provide
a large amount of experimental data on them, contributing to our understanding of
the molecular basis responsible for their function and filling a gap of about 50 years
with respect to our knowledge on the structural and dynamic behaviour of folded
proteins. This is expected to reveal a much larger number of ways in which proteins
communicate in the cell. Other expected outcomes of NMR experimental data on
Preface vii
IDPs include the improvement of prediction tools, which still suffer from the bias
that they are derived from the missing information in the electron density maps in
X-ray crystallography data!
We hope you will enjoy the book, and even more studying IDPs through NMR,
as much as we do! A great thanks to all the Authors that we had the luck to work
with and to the IDPbyNMR EC Marie Curie Initial Training Network which con-
tributed to make it possible.
Contents
1 Back to the Future: Nuclear Magnetic Resonance and
Bioinformatics Studies on Intrinsically Disordered Proteins .............. 1
A. Keith Dunker and Christopher J. Oldfield
2 Structure and Dynamics of Intrinsically Disordered Proteins ............ 35
Biao Fu and Michele Vendruscolo
3 NMR Methods for the Study of Instrinsically Disordered
Proteins Structure, Dynamics, and Interactions: General
Overview and Practical Guidelines ........................................................ 49
Bernhard Brutscher, Isabella C. Felli, Sergio Gil-Caballero,
Tomáš Hošek, Rainer Kümmerle, Alessandro Piai, Roberta
Pierattelli and Zsófia Sólyom
4 Ensemble Calculation for Intrinsically Disordered Proteins
Using NMR Parameters .......................................................................... 123
Jaka Kragelj, Martin Blackledge and Malene Ringkjøbing Jensen
5 NMR Spectroscopic Studies of the Conformational
Ensembles of Intrinsically Disordered Proteins .................................... 149
Dennis Kurzbach, Georg Kontaxis, Nicolas Coudevylle
and Robert Konrat
6 Recombinant Intrinsically Disordered Proteins for NMR:
Tips and Tricks ......................................................................................... 187
Eduardo O. Calçada, Magdalena Korsak and Tatiana Kozyreva
7 Biophysical Methods to Investigate Intrinsically Disordered
Proteins: Avoiding an “Elephant and Blind Men” Situation ............... 215
Vladimir N. Uversky
ix
x Contents
8 A pplication of SAXS for the Structural Characterization of IDPs ..... 261
Michael Kachala, Erica Valentini and Dmitri I. Svergun
9 Bioinformatics Approaches for Predicting Disordered
Protein Motifs ........................................................................................... 291
Pallab Bhowmick, Mainak Guharoy and Peter Tompa
10 Towards Understanding Protein Disorder In-Cell ................................ 319
Cesyen Cedeño, Hadas Raveh-Amit, András Dinnyés
and Peter Tompa
11 T he Protein Ensemble Database ............................................................. 335
Mihaly Varadi and Peter Tompa
12 Order and Disorder in the Replicative Complex
of Paramyxoviruses .................................................................................. 351
Jenny Erales, David Blocquel, Johnny Habchi,
Matilde Beltrandi, Antoine Gruet, Marion Dosnon,
Christophe Bignon and Sonia Longhi
13 Druggability of Intrinsically Disordered Proteins ................................ 383
Priyanka Joshi and Michele Vendruscolo
14 Beta Amyloid Hallmarks: From Intrinsically Disordered
Proteins to Alzheimer’s Disease .............................................................. 401
Magdalena Korsak and Tatiana Kozyreva