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ADVANCES IN PROTEIN CHEMISTRY

Volume 61

Protein Modules and Protein±Protein Interaction

This Page Intentionally Left Blank
 ADVANCES IN
PROTEIN CHEMISTRY
EDITED BY
FREDERIC M. RICHARDS DAVID S. EISENBERG
Department of Molecular Biophysics Department of Chemistry and Biochemistry
and Biochemistry University of California, Los Angeles
Yale University Los Angeles, California
New Haven, Connecticut

JOHN KURIYAN
Department of Molecular and Cellular Biology
University of California, Berkeley
Berkeley, California

VOLUME 61

Protein Modules and

Protein±Protein Interaction

EDITED BY

JOEÈL JANIN
Laboratoire d'Enzymologie et Biochimie Structurales
C.N.R.S., Gif-sur-Yvette, France

SHOSHANA J. WODAK
Unite de Conformation de MacromoleÂcules Biologique
Universite Libre de Bruxelles, Brussels, Belgium

Amsterdam Boston London New York Oxford Paris

San Diego San Francisco Singapore Sydney Tokyo
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 CONTENTS

Introduction

JOEÈL JANIN AND SHOSHANA J. WODAK

I. Protein Modules and Protein±Protein Interaction:

Toward a Global View . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Web Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Structural Basis of Macromolecular Recognition

SHOSHANA J. WODAK AND JOEÈL JANIN

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
II. Geometric and Chemical Features of
Macromolecular Recognition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
III. Classi®cation of Protein±Protein and Protein±DNA
Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
IV. Energetics of Macromolecular Recognition. . . . . . . . . . . . . . . . . . . . . . . 40
V. Computational Approaches for Predicting and Simulating
Protein±Protein Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
VI. Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Web Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Sequence Analysis of Multidomain Proteins: Past Perspectives

and Future Directions

RICHARD R. COPLEY, CHRIS P. PONTING, JOÈRG SCHULTZ, AND PEER BORK

I. Identi®cation of Novel Protein Domain Families . . . . . . . . . . . . . . . . . 75

II. Methods for Classifying Protein Domain Families . . . . . . . . . . . . . . . . 81
III. From Domain Classi®cation to Domain Context . . . . . . . . . . . . . . . . . . 85
IV. Genome-Wide Analysis: New Quality in Domain Research . . . . . . . . 89

v
vi CONTENTS

V. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Identi®cation of Transiently Interacting Proteins and of Stable

Protein Complexes

BERTRAND SEÂRAPHIN

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
II. Genetic Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
III. Biological Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
IV. Biochemical Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
V. Validation of Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
VI. Characterization of Interacting Subunits and Dissection
of Interaction Domains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Molecular Recognition in Antibody±Antigen Complexes

ERIC J. SUNDBERG AND ROY A. MARIUZZA

I.Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
II.Structure of Antibody±Antigen Interfaces. . . . . . . . . . . . . . . . . . . . . . 121
III.Antibody Cross-Reactivity and Molecular Mimicry . . . . . . . . . . . . . 125
IV.Thermodynamic Mapping of Antigen±Antibody Interfaces . . . . . 132
V.Dissection of Binding Energetics in Antigen±Antibody
Interfaces Using Double-Mutant Cycles . . . . . . . . . . . . . . . . . . . . . . . 136
VI. Accommodation of Mutations in Antigen±Antibody Interfaces . . 144
VII. Functional Roles for Protein Plasticity in Antigen Recognition . . 148
VIII. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Molecular Recognition by SH2 Domains

J. MICHAEL BRADSHAW AND GABRIEL WAKSMAN

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
II. Single SH2 Domain Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
III. Functional Analysis of Single SH2 Domain Binding . . . . . . . . . . . . 172
IV. Structure and Function of SH2 Domains in the Context of
Other Protein Modules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
 CONTENTS vii

V. Unusual SH2 Domain Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

VI. SH2 Domains as Drug Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
VII. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

How SH3 Domains Recognize Proline

ANDREA MUSACCHIO

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
II. Proline and Polyproline Type II Helices . . . . . . . . . . . . . . . . . . . . . . . . 212
III. The SH3 Domain: A Model System to Understand Interactions
Mediated by Proline-Rich PPH Helices . . . . . . . . . . . . . . . . . . . . . . . . . 215
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

Structural Biology of eIF4F: mRNA Recognition and Preparation

in Eukaryotic Translation Initiation

JOSEPH MARCOTRIGIANO AND STEPHEN K. BURLEY

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
II. Structural Features of Eukaryotic mRNAs. . . . . . . . . . . . . . . . . . . . . . . 271
III. General Mechanisms of Cellular, Cap-Dependent
Translation Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
IV. HEAT Repeats within eIF4G Direct Assembly of
Translation Machinery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
V. Preparation of the mRNA 5'-UTR for Small Ribosomal
Subunit Binding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
VI. Conclusion and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

AUTHOR INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

SUBJECT INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
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 INTRODUCTION
È L JANIN* AND SHOSHANA J. WODAK²
BY JOE

* Laboratoire d'Enzymologie et Biochimie Structurales,

CNRS UPR9063, 91198 Gif-sur-Yvette, France, and ² Unite de Conformation
de MacromoleÂcules Biologique,
Universite Libre de Bruxelles CP 160/16, 1050 Brussels, Belgium

I. Protein Modules and Protein±Protein Interaction: Toward a Global View . . . . . . 1

Web Sites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

I. PROTEIN MODULES AND PROTEIN±PROTEIN INTERACTION:

TOWARD A GLOBAL VIEW

As this volume was being assembled, the completion of the DNA

sequence of the human genome was reported by the International
Human Genome Sequencing Consortium (2001) and by Venter et al.
(2001). This is a major hallmark of biology, which brings to the forefront
the vast new potential and momentous challenges that the knowledge of
whole genome sequences is offering. A hundred or so complete genomes,
of species ranging from bacteria to human, have now been sequenced,
and many more are in the pipeline (NCBI Genomic Biology Web site).
This ¯ow of information is changing the way in which research in all
®elds of biology is performed. Until recently most biochemists and mo-
lecular biologists focused on the properties of single genes and proteins
involved in individual biological processes. Now it becomes possible to
study how individual genes and gene products cooperate to build up
complex cellular structures and to perform all the elaborate processes
that enable cells and organisms to live and reproduce themselves.
Before this vast new potential can be exploited, however, the genome
sequence information must be decoded in terms of biological function.
This endeavor, termed functional genomics, is the new challenge that
immediately follows that of sequencing the human genome. It deals with
gene products rather than genes, and because nearly all the gene prod-
ucts are proteins, the center of interest is shifting from DNA to RNA
to proteins. After a major effort in DNA sequencing, we are hence
witnessing a major effort in proteomics, the analysis of the proteome,
de®ned as the complement of proteins in a cell. Proteomics encompasses
many aspects, ranging from the identi®cation and quanti®cation of
proteins at the cellular level to the analysis of their functional and physical
interactions, as well as their molecular structure and function (Fields,
2001).

1
Copyright 2003, Elsevier Science (USA).
ADVANCES IN All rights reserved.
PROTEIN CHEMISTRY, Vol. 61 0065-3233/03 $35.00
2 È L JANIN AND SHOSHANA J. WODAK
JOE

One key result of the genome sequencing work is the relatively small
number of genes needed to build a living organism. An organism can
live a parasitic life with only a few hundred genes (Mycoplasma). It can
perform elaborate chemistry and physiology with a few thousands
(Escherichia coli Bacillus subtilis, Saccharomyces cerevisiae, and many other
unicellular species) and is able to develop into a complete plant or animal
with a few tens of thousands (Arabidopsis thaliana, Caenorhabditis elegans, or
Drosophila melanogaster). In the human genome, no more than 30,000±
40,000 protein-coding genes can be identi®ed at present, a mere one-
third more than the number of genes in the worm C. elegans (C. elegans
Sequencing Consortium, 1998).
This clearly suggests that the complexity of living organisms is not simply
correlated to the number of protein-coding genes. We know of mechan-
isms that increase the number of chemically distinct proteins beyond the
number of genes. Alternative splicing of messenger RNA is one; posttran-
slational modi®cations of the polypeptide chains may be another. But the
major source of complexity in an organism must be combinatorial, rather
than proportional to the complexity of its genome. Combinatorial com-
plexity is an expected consequence of the implication of many gene prod-
ucts in each physiological process, with elaborate regulations at both the
gene and protein levels, which remain largely unexplored.
At the molecular level, complexity in the living cell derives ®rst from
the many different interactions that proteins can undergo. The immense
variety of biological functions performed by proteins essentially depends
on the molecular interactions that they make and on the cellular context
in which they ®nd themselves. Each protein is designed to speci®cally
bind one or several small molecules, nucleic acids, and other proteins.
Thus, the analysis of protein interactions, a major theme of this volume, is
becoming a main focus of attention in the postgenomic era. Efforts in this
area include the systematic identi®cation of all the constituents of large
protein complexes (Neubauer et al., 1998; Peltier et al., 2000; Rout et al.,
2000; Gaven et al., 2002; Ho et al., 2002) and attempts to map by genetic
assays the complete repertoire of protein±protein interactions that occur
in a cell. The already classical yeast two-hybrid method (Fields and Song,
1989) is being complemented by others, the split ubiquitin system (Stagl-
jar et al., 1998), for instance. The biochemical approach combines estab-
lished experimental techniques, such as chromatography and gel
electrophoresis for preparing complexes, with ultrasensitive methods
of mass spectrometry to identify their components (Link et al., 1999;
Washburn et al., 2001). These techniques, discussed in the chapter by
Seraphin in this volume, are being combined in new ways, scaled up, and
overhauled to face the challenge of identifying components of large
assemblies available in trace amounts.
 INTRODUCTION 3

Large sets of data are being generated by these genetic and biochem-
ical methods and specialized databases are being developed to manage
them. These include the Database of Interacting Proteins developed by
Eisenberg and colleagues in the United States (Xenarios et al., 2000) and
the Biomolecular Interaction Network Database developed by Hogue
and collaborators in Canada (see Bader et al., 2001). For instance, system-
atic screens of interacting proteins in the yeast S. cerevisiae performed by
different authors have produced networks containing thousands of inter-
acting pairs (Schwikowski et al., 2000; Uetz et al., 2000; Ito et al., 2001).
The same approach is being pursued in other organisms (Walhout et al.,
2000; Rain et al., 2001). In yeast, there is very little overlap between the
networks of interactions derived by different authors, and one likely
reason is that the number of interactions that actually exist in the cell is
so large that each experiment detects only a small fraction of them
(Hazbun and Fields, 2001). The challenge is thus once again in the
interpretation of the data. Are all the detected interactions biologically
and functionally meaningful? And, if not, how can we ef®ciently single
out the meaningful ones from the others? Are we missing key interactions
that go undetected by these approaches? Answering these questions
requires some understanding of the basic physical principles that govern
protein±protein recognition and macromolecular recognition in general
at the molecular and atomic level.
Many systems have already been studied in great detail. Of particular
interest is the recognition of a protein antigen by an antibody. This binary
interaction is analyzed in the chapter by Sundberg and Mariuzza in this
volume. The antibody moiety of antigen±antibody recognition always
involves the same protein component made of a pair of variable immuno-
globulin domains. Signal transduction in eukaryotic cells also relies on
binary protein±protein recognition, but it involves a cascade of recogni-
tion steps and many different types of proteins: receptors, enzymes,
adaptors, transcription factors, etc. The chapter on Sarc-homology 2
(SH2) domains by Bradshaw and Waksman and the chapter on polypro-
line recognition by Musacchio describe some of the steps in signal trans-
duction and the proteins that perform these steps. In antigen±antibody
recognition and in signal transduction, a large body of data has been
derived from the structural, biochemical, and theoretical analyses of
protein±protein complexes. In other processes, the information may be
equally rich, but far less complete. Gene transcription in eukaryotic cells
is an example. It involves several levels of regulation and is performed by
large macromolecular assemblies, which we are just barely starting to
understand. This is a very active ®eld of study, illustrated in this volume
in the chapter by Marcotrigiano and Burley on initiation factor eIF4F.
In all these systems, the knowledge of the three-dimensional structure
4 È L JANIN AND SHOSHANA J. WODAK
JOE

derived from X-ray crystallography is the starting point for biochemical

and physical chemical studies, and, thanks to these studies, recognition
can be said to be understood at the atomic level. There are many other
cellular processes for which this information is not yet available. Never-
theless, biologists at large should be aware of this work and use it to
correctly extrapolate from the in vitro observations to the in vivo proper-
ties and to design better experiments for systematically analyzing inter-
actions in a cell.
Protein modules, another focus of this volume, are involved in all of
the above-mentioned interactions and processes. The word ``module'' is a
general designation for recurrent protein fragments that have a distinct
structure, function, and/or evolutionary history. Examples are the im-
munoglobulin domains or the SH2 domains. The chapter by Copley and
collaborators in this volume reviews the fruitful interplay of studies in
protein sequence, three-dimensional structure, and function, which leads
to the description of proteins as modular entities. Structural domains
were initially de®ned as segments of the polypeptide chain that fold
into globular units, but they may also carry out specialized molecular
functions (Wetlaufer, 1973; Rose, 1979; Janin and Wodak, 1983). When
the same or a closely similar domain is found in many different proteins,
it becomes a module. Whereas the three-dimensional structure is con-
served in these different contexts, the aminoacid sequence, and occasion-
ally the function, may differ substantially. Recent analyses of known
genomes con®rm that organisms as diverse as bacteria and humans
share many proteins and protein domains and give strong support
to the view the that total number of gene/protein modules is small.
Before any genome sequence was completed, Chothia estimated the
total number of different folds that protein domains can adopt to be
no more than 1000 (Chothia, 1992). More recent estimates are in the
range 1000±6000 (Orengo et al., 1994; Brenner et al., 1997). Many
of these domains are highly recurrent and may therefore be called
modules.
Modules can exist as such, forming a small single-domain protein. Most
of the time, however, they are part of larger polypeptide chains, assem-
bled by successive events of gene fusion. Combining a speci®c set of
modules within a single polypeptide chain ensures that they are ex-
pressed together and localized in the same cells or cellular compartments
(Tsoka and Ouzounis, 2000). Alternatively, the modules may participate
in the same cellular process and sometimes interact physically, forming
speci®c protein±protein complexes, without being linked covalently. Both
the fused and the separated arrangements exist in nature. While the
former is observed in some organisms, the latter is likely to be used in
others. This is the basis of a method for detecting protein±protein inter-
 INTRODUCTION 5

actions proposed by Marcotte and collaborators at UCLA (Marcotte et al.,

1999a, b). Ouzounis and collaborators at EBI-EMBL (Hinxton, UK) have
performed a similar analysis (Enright et al., 1999). Although it is at
present not clear what fraction of the interactions detected by these
approaches represent actual physical interactions between the protein
modules, there is mounting evidence that these methods detect their
involvement in common functional processes. Whether the genes are
fused or separate, there is a very close interplay between protein modules
and their interactions at the functional or physical level.
Our understanding of evolution at the molecular and cellular levels
and our ability to understand, modify, and one day simulate cellular
function will crucially depend on our knowledge of the rules of this
game. This is prompting attempts to capture some of the global patterns
of the protein±protein interaction networks determined from the two-
hybrid screens (Schwikowski et al., 2000; Jeong et al., 2001) to map data
from these experiments onto the network of cellular processes or to link
information on the function and evolution of individual protein modules
with that on the physical interactions between these modules (Park et al.,
2001). Figure 1 illustrates graphically one such attempt. Once the net-
works are established, atomic structures and thermodynamic parameters
for the interacting protein pairs will still be required to validate data
produced by genome±scale experiments and to give a molecular basis
to the networks.
Protein±protein interaction is becoming a major theme of the postge-
nome era, and its study constitutes an essential component of functional
genomics. We hope that this volume will help bring biologists and
physical chemists together. Their respective approaches are comple-
mentary and should thus never be more productive than when they are
combined.

WEB SITES

Biomolecular Interaction Network Database (Toronto, Ontario, Canada), http://

www.bind.ca.
Database of Interacting Proteins (UCLA, CA), http://www.doe-mbi.ucla.edu.
Macromolecular Structure Database (EBI-EMBL, Hinxton, UK), http://pdb-browsers.ebi.
ac.uk.
NCBI Genomic Biology (National Center for Biotechnology Information, Bethesda, MD),
http://www.ncbi.nlm.nih.gov/Genomes.
Protein Data Bank (Research Collaboratory for Structural Bioinformatics, Rutgers Univer-
sity, New Brunswick, NJ), http:// www.rcsb.org/pdb.
Structural Classi®cation of Proteins (MRC-LMB, Cambridge, UK), http://scop.mrc-lmb.
cam.ac.uk/scop/.
6 È L JANIN AND SHOSHANA J. WODAK
JOE

FIG. 1. Global network of protein±protein interaction in yeast built from data on

two-hybrid screens [reproduced with permission from Jeong et al. (2001) ]. Nodes are
colored according to the phenotypic effect of removing the corresponding protein
from the organism (red, lethal; green, nonlethal; orange, slow growth; yellow, un-
known).

REFERENCES

Bader, G. D., Donaldson, I., Wolting, C., Ouellette, B. F., Pawson, T., and Hogue, C. W.
(2001). BINDÐThe Biomolecular Interaction Network Database. Nucleic Acids Res. 29(1),
242±245.
Brenner, S. E., Chothia, C., and Hubbard, T. J. (1997). Population statistics of pro-
tein structures: Lessons from structural classi®cations. Curr. Opin. Struct. Biol. 7(3),
369±376.
C. elegans Sequencing Consortium (1988). Genome sequence of the nematode C. elegans: A
platform for investigating biology. Science 282(5396), 2012±2018.
Chothia, C. (1992). Proteins: One thousand families for the molecular biologist. Nature
357(6379), 543±544.
Enright, A. J., Iliopoulos, I., Kyrpides, N. C., and Ouzounis, C. A. (1999). Protein interaction
maps for complete genomes based on gene fusion events. Nature 402(6757), 86±90.
Fields, S. (2001). Proteomics. Proteomics in genomeland. Science 291(5507), 1221±1224.
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