Transcript ppt

V3 From Protein Complexes to Networks and back
Protein networks could be defined in a number of ways
(1) Co-regulated expression of genes/proteins
(2) Proteins participating in the same metabolic pathways
(3) Proteins sharing substrates
(4) Proteins that are co-localized
(5) Proteins that form permanent supracomplexes = „protein machines“
(6) Proteins that bind each other transiently
(signal transduction, bioenergetics ... )
In V4 we will look at computational methods to predict protein-protein interactions.
Today, we will look at permanent and transient protein complexes.
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Methods for the structural characterization of macromolecular assemblies
(a) Electron diffraction map and 3D X-ray protein structure. X-ray provides atomic-resolution structures.
(b) 3D protein structure and plot showing chemical shifts determined by NMR. NMR spectroscopy extracts distances between
atoms by measuring transitions between different nuclear spin states within a magnetic field. These distances are then used as
restraints to build 3D structures. NMR spectroscopy also provides atomic-resolution structures, but is generally limited to proteins
of about 300 residues. It plays an increasingly important role in studying interaction interfaces between structures determined
independently.
(c) EM micrograph and 3D reconstruction of a virus capsid. EM is based on the analysis of images of stained particles. Different
views and conformations of the complexes are trapped and thus thousands of images have to be averaged to reconstruct the
three-dimensional structure. Classical implementations were limited to a resolution of 20 Å. More recently, single-particle cryo
techniques, whereby samples are fast frozen before study, have reached resolutions as high as approximately 6 Å. EM provides
information about the overall shape and symmetry of macromolecules.
(d) Slice images and rendered surface of a ribosome-decorated portion of endoplasmic reticulum. In electron tomography, the
specimen studied is progressively tilted upon an axis perpendicular to the electron beam. A set of projection images is then
recorded and used to build a 3D model. This technique can tackle large organelles or even complete cells without perturbing
their physiological environment. It provides shape information at resolutions of approximately 30 Å.
(e) Yeast two-hybrid array screen and small network of interacting proteins. Interaction discovery comprises many different
methods whose objective is to determine spatial proximity between proteins. These include techniques such as the two-hybrid
system, affinity purification, FRET, chemical cross-linking, footprinting and protein arrays. These methods provide very limited
structural information and no molecular details. Their strength is that they often give a quasi-comprehensive list of protein
interactions and the networks they form.
Russell et al. Curr. Opin. Struct. Biol. 14, 313 (2004)
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Hybrid models: docking X-ray structures into EM maps
Hybrid assembly of the 80S ribosome from yeast.
(a) Superposition of a comparative protein structure model (red) of a domain
from ribosomal protein L2 from Bacillus stearothermophilus with the actual
structure (blue) (PDB code 1RL2).
(b) A partial molecular model of the whole yeast ribosome calculated by fitting
atomic rRNA (not shown) and comparative protein structure models (ribbon
representation) into the electron density of the 80S ribosomal particle.
Russell et al. Curr. Opin. Struct. Biol. 14, 313 (2004)
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Putative structure through modeling and low-resolution EM
(a) Exosome subunits. The top of the panel shows the domain organization of two subunits
present in the complex, but lacking any detectable similarity to known 3D structures. The
model for the nine other subunits (bottom) was constructed by predicting binary interactions
using InterPReTS and building models based on a homologous complex structure using
comparative modeling.
(b) EM density map (green mesh) with the best fit of the model shown as a gray surface
and the predicted locations of the subunits labeled. The question marks indicate those
subunits for which no structures could be modeled.
Russell et al. Curr. Opin. Struct. Biol. 14, 313 (2004)
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Potential errors in biochemical interaction discovery
(b) An example of an interaction that is not
detected by any screen, possibly because
molecular labels (e.g. affinity purification tags,
or two-hybrid DNA binding or activation
domains) are interfering with the interaction.
The X-ray structure of the actin–profilin
complex reveals that the actin C terminus (Ct) lies at the interaction interface (the other N
and C termini are also labeled).
(a) Indirect interactions between
cyclin-dependent kinase regulatory
subunit (CKS) and cyclin A detected
by the Y2H system.
Several interactions between CKS
domains and cyclins were reported in
genome-scale two-hybrid studies.
However, analysis of 3D structures
suggests that the endogenous cyclindependent kinase 2 (CDK2) probably
mediates the interaction, as
combining the CDK2–CKS and
CDK2–cyclin A structures places the
CKS and cyclin domains 18 Å apart.
Russell et al. Curr. Opin. Struct. Biol. 14, 313 (2004)
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1 Protein-Protein Complexes
It has been realized for quite some time that cells don‘t work by random
diffusion of proteins,
but require a delicate structural organization into large protein complexes.
Which complexes do we know?
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RNA Polymerase II
RNA polymerase II is the
central enzyme of gene
expression and synthesizes all
messenger RNA in
eukaryotes.
Cramer et al., Science 288, 640 (2000)
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RNA processing: splicesome
Structure of a cellular editor that "cuts and pastes" the first draft of RNA straight
after it is formed from its DNA template. It has two distinct, unequal halves
surrounding a tunnel. The larger part appears to contain proteins and the short
segments of RNA, while the smaller half is made up of proteins alone. On one
side, the tunnel opens up into a cavity, which the researchers think functions as
a holding space for the fragile RNA waiting to be processed in the tunnel itself.
Profs. Ruth and Joseph Sperling
http://www.weizmann.ac.il/
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Protein synthesis: ribosome
The ribosome is a complex
subcellular particle composed of
protein and RNA. It is the site of
protein synthesis,
Model of a ribosome with a
newly manufactured protein
(multicolored beads) exiting
on the right.
http://www.millerandlevine.com/chapter/12
/cryo-em.html
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Signal recognition particle
40S small ribosomal subunit
(yellow) 60S large ribosomal
subunit (blue), P-site tRNA (green),
SRP (red).
Halic et al. Nature 427, 808 (2004)
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Cotranslational translocation of proteins across or into membranes is
a vital process in all kingdoms of life. It requires that the translating
ribosome be targeted to the membrane by the signal recognition
particle (SRP), an evolutionarily conserved ribonucleoprotein
particle. SRP recognizes signal sequences of nascent protein chains
emerging from the ribosome. Subsequent binding of SRP leads to a
pause in peptide elongation and to the ribosome docking to the
membrane-bound SRP receptor. SRP shows 3 main activities in the
process of cotranslational targeting: first, it binds to signal sequences
emerging from the translating ribosome; second, it pauses peptide
elongation; and third, it promotes protein translocation by docking to
the membrane-bound SRP receptor and transferring the ribosome
nascent chain complex (RNC) to the protein-conducting channel.
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Nuclear Pore Complex
A three-dimensional image of the
nuclear pore complex (NPC),
revealed by electron microscopy.
A-B The NPC in yeast.
Figure A shows the NPC seen
from the cytoplasm while figure B
displays a side view.
C-D The NPC in vertebrate
(Xenopus).
NPC is a 50-100 MDa protein assembly that
regulates and controls trafficking of
macromolecules through the nuclear envelope.
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http://www.nobel.se/medicine/educational/dn
a/a/transport/ncp_em1.html
Three-Dimensional Architecture of the
Isolated Yeast Nuclear Pore Complex:
Functional and Evolutionary Implications,
Qing Yang, Michael P. Rout and Christopher
W. Akey. Molecular Cell, 1:223-234, 1998
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GroEL: a chaperone to assist misfolded proteins
Ransom et al., Cell 107, 869 (2001)
Schematic Diagram of GroEL Functional States
(a) Nonnative polypeptide substrate (wavy black line) binds
to an open GroEL ring. (b) ATP binding to GroEL alters its
conformation, weakens the binding of substrate, and
permits the binding of GroES to the ATP-bound ring.
(c) The substrate is released from its binding sites and
trapped inside the cavity formed by GroES binding.
(d) Following encapsulation, the substrate folds in the
cavity and ATP is hydrolysed.
(e) After hydrolysis in the upper, GroES-bound ring, ATP
and a second nonnative polypeptide bind to the lower ring,
discharging ligands from the upper ring and initiating new
GroES binding to the lower ring (f) to form a new folding
active complex on the lower ring and complete the cycle.
http://people.cryst.bbk.ac.uk/~ubcg16z/chaperone.html
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Arp2/3 complex
The seven-subunit Arp2/3 complex choreographs the formation of branched actin
networks at the leading edge of migrating cells.
(A) Model of actin filament branches mediated by Acanthamoeba Arp2/3 complex.
(D) Density representations of the models of actin-bound (green) and the free, WAactivated (as shown in Fig. 1D, gray) Arp2/3 complex.
Volkmann et al., Science 293, 2456 (2001)
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proteasome
The proteasome is the central
enzyme of non-lysosomal protein
degradation. It is involved in the
degradation of misfolded proteins
as well as in the degradation and
processing of short lived regulatory
proteins.The 20S Proteasome
degrades completely unfoleded
proteins into peptides with a
narrow length distribution of 7 to
13 amino acids.
http://www.biochem.mpg.de/xray/projects/hu
bome/images/rpr.gif
Löwe, J., Stock, D., Jap, B., Zwickl, P.,
Baumeister, W. and Huber, R. (1995). Crystal
structure of the 20S proteasome from the
archaeon T. acidophilum at 3.4 Å resolution.
Science 268, 533-539.
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Energy conversion: Photosynthetic Unit
Other large complexes:
Structure suggested by
force field based
molecular docking.
- Apoptosome
-Thermosome
- Transcriptome
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http://www.ks.uiuc.edu/Research/vmd/gallery
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icosahedral pyruvate dehydrogenase complex:
a multifunctional catalytic machine
Milne et al., EMBO J. 21, 5587 (2002)
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Model for active-site coupling in the E1E2 complex. 3 E1
tetramers (purple) are shown located above the
corresponding trimer of E2 catalytic domains in the
icosahedral core. Three full-length E2 molecules are
shown, colored red, green and yellow. The lipoyl domain of
each E2 molecule shuttles between the active sites of E1
and those of E2. The lipoyl domain of the red E2 is shown
attached to an E1 active site. The yellow and green lipoyl
domains of the other E2 molecules are shown in
intermediate positions in the annular region between the
core and the outer E1 layer. Selected E1 and E2 active
sites are shown as white ovals, although the lipoyl domain
can reach additional sites in the complex.
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Apoptosome
(A) Top view of the apoptosome along the 7-fold
symmetry axis.
(B) Details of the spoke.
(C) A side view of the apoptosome reveals the
unusual axial ratio of this particle. The scale bar is
100 Å.
(D) An oblique bottom view shows the puckered
shape of the particle. The arms are bent at an
elbow (see asterisk) located proximal to the hub.
Acehan et al. Mol. Cell 9, 423 (2002)
Apoptosis is the dominant form of programmed cell death during embryonic development and normal tissue turnover. In
addition, apoptosis is upregulated in diseases such as AIDS, and neurodegenerative disorders, while it is downregulated in
certain cancers. In apoptosis, death signals are transduced by biochemical pathways to activate caspases, a group of proteases
that utilize cysteine at their active sites to cleave specific proteins at aspartate residues. The proteolysis of these critical proteins
then initiates cellular events that include chromatin degradation into nucleosomes and organelle destruction. These steps
prepare apoptotic cells for phagocytosis and result in the efficient recycling of biochemical resources.
In many cases, apoptotic signals are transmitted to mitochondria, which act as integrators of cell death because both effector
and regulatory molecules converge at this organelle. Apoptosis mediated by mitochondria requires the release of cytochrome c
into the cytosol through a process that may involve the formation of specific pores or rupture of the outer membrane.
Cytochrome c binds to Apaf-1 and in the presence of dATP/ATP promotes assembly of the apoptosome. This large protein
complex then binds and activates procaspase-9.
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Future?
Structural genomics (X-ray) may soon generate enough templates of individal
folds.
Structural genomics may be expanded to protein complexes.
Interactions between proteins of the same fold tend to be similar when the
sequence identity is above approximately 30% (Aloy et al.).
Hybrid modelling of X-ray/EM will not be able to answer all questions
- problem of induced fit
- transient complexes cannot be addressed by these techniques
 Essential to combine large variety of hybrid + complementary methods
Russell et al. Curr. Opin. Struct. Biol. 14, 313 (2004)
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2 Information on protein-protein networks
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2. Yeast 2-Hybrid Screen
Data on protein-protein
interactions from
Yeast 2-Hybrid Screen.
One role of bioinformatics is to
sort the data.
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Protein cluster in yeast
Cluster-algorithm
generates one large
cluster for proteins
interacting with each
other based on
binding data of
yeast proteins.
Schwikowski, Uetz, Fields, Nature Biotech. 18, 1257 (2001)
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Annotation of function
After functional annotation:
connect clusters of
interacting proteins.
Schwikowski, Uetz, Fields, Nature Biotech. 18, 1257 (2001)
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Annotation of localization
Schwikowski, Uetz, Fields, Nature Biotech. 18, 1257 (2001)
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3 Systematic identification of protein complexes
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Systematic identication of large protein complexes
Yeast 2-Hybrid-method can only identify binary complexes.
Cellzome company: attach additional protein P to particular protein Pi ,
P binds to matrix of purification column.
 yields Pi and proteins Pk bound to Pi .
Identify proteins
by mass spectrometry (MALDITOF).
Gavin et al. Nature 415, 141 (2002)
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Analyis of protein complexes in yeast (S. cerevisae)
Identify proteins by
scanning yeast protein
database for protein
composed of fragments
of suitable mass.
Here, the identified
proteins are listed
according to their
localization (a).
(b) lists the number of
proteins per complex.
Gavin et al. Nature 415, 141 (2002)
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Validation of methodology
Check of the method: can the same
complex be obtained for different
choice of attachment point
(tag protein attached to different
coponents of complex)? Yes (see gel).
Method allows to identify components
of complex, not the binding interfaces.
Better for identification of interfaces:
Yeast 2-hybrid screen (binary interactions).
3D models of complexes are important
to develop inhibitors.
Gavin et al. Nature 415, 141 (2002)
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- theoretical methods (docking)
- electron tomography
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Analysis of affinity-purified protein complexes in E.coli
TAP-purification for 25% of the E.coli genome, targeting 1000 ORFs.
 857 tagged proteins, including 198 essential and conserved proteins
 648 could be purified.
Out of these, 118 had no detectable partners.
530 other „baits“ : 5254 protein-protein interactions.
Verification by reciprocal tagging of many candidate partners: 53% validation rate
(716 non-redundant validated interactions).
85% of the validated interactions are new! Not described in the Database of
Interacting Proteins (DIP), Biomolecular Interaction Network Database (BIND),
and other databases.
Butland et al. Nature 433, 531 (2005)
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Pilot purification of DNA-dependent RNA polymerase
SDS–PAGE silver-stain analysis of the
components of affinity-purified complexes from E.
coli.
a–c, Purification of TAP-tagged E. coli RNAP
subunit b (a) and two associated proteins: SPAtagged b1731 (b) and TAP-tagged YacL (c).
a Tagged core subunit  of RNA polymerase (RpoB) co-purified specifically with
essential elongation factors (NusA and NusG), specified sigma factors involved in
promoter recognition (RpoH, RpoS, RpoD) and with accessory factors (RpoZ, HepA
and YacL).
Similarly, NusG was co-purified with YacL, HepA, core enzyme and termination factor
Rho, whereas RpoZ bound RpoD, NusA and b1731 (sofar unknown).
b reciprocal experiment: tagged b1731 co-purified with , RpoC, RpoA, RpoD and
RpoZ, but not with Nus factors, HepA or YacL.  probably b1731 exclusively
binds to , suggesting an exclusive association with initiating holoenzyme.
c However, tagged YacL bound RpoZ, NusG and HepA together with core enzymes,
suggesting a role in elongation.
Butland et al. Nature 433, 531 (2005)
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Network properties of bacterial protein-protein interactions
Network of validated protein
complexes. Interactions are
represented as directional
edges extending from the
tagged protein.
Baits without partners are
removed for clarity.
Red nodes, essential proteins;
blue nodes, non-essential
proteins;
black ovals, complexes
discussed in text.
Butland et al. Nature 433, 531 (2005)
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Significance of novel interactions?
Check functional annotation
E.g., acyl carrier protein (ACP), a key carrier of growing fatty acid chains,
bound specifically and reproducibly to enzymes linked to biogenesis of
fatty acids, phospholipids and lipid A (essential outer-membrane
constituent), including
- two 3-ketoacyl-ACP synthases (FabB, FabF)
- 3-ketoacyl-ACP reductase (FabG),
- 3-hydroxyacyl-ACP dehydrase (FabZ),
- LpxD (essential protein required for lipid A biogenesis),
- YbgC (tol-pal cluster hydrolase of short-chain acyl-CoA thioesters),
- AcpS (involved in transfer of 4‘ - phosphopantethein to ACP),
- Aas and PlsB (membrane proteins involved in phospholipid acylation),
and
- YiiD (putative acetyltransferase).
ACP also co-purified with GlmU (an essential bi-functional
enzyme that converts glucosamine-1-phosphate to UDP-GlcNAc
(lipid A precursor)), AidB (isovaleryl-CoA dehydrogenase), SecA
(pre-protein translocase), as well as MukB and SpoT.
Butland et al. Nature 433, 531 (2005)
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Network properties of bacterial protein-protein interactions
Connectivity distribution of
validated interactions (K) per
protein plotted as a function of
frequency, P(k).
Inset: log-plot power law
distribution, P(k) < k-, where 
is the degree exponent.
 evidence of „scale-free behavior“
Comparable connectivity observed for the essential-conserved proteins alone.
Butland et al. Nature 433, 531 (2005)
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Interaction network connectivity and robustness
Node shading (white to black) is scaled according to the increasing number of
genomes in which a putative interaction is detected based on gene co-occurrence.
a, Interaction network after attacking the 20 most highly connected, highly
conserved (detected by BLAST in >= 125 genomes) hubs.
b, Network before attack (See Fig 3c).
 removal of 20 hubs markedly reduced network connectivity.
Butland et al. Nature 433, 531 (2005)
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Interaction network connectivity and robustness
c Connectivity properties of the conserved (blue color; detected by BLAST in >= 125 genomes)
and non conserved (purple color; <= 25 genomes) proteins.
Hubs are all conserved!
x-axis: number of connections per protein
y-axis: frequency of proteins belonging to this group.
Inset: mean of random sets of interacting proteins (Control) of the same size as the datasets.
d, x-axis: number of interactions per protein
y-axis: number of genomes a homolog was detected in (BLAST score ≥ 50).
Protein connectivity is proportional to the number of homologous
in other genomes
Butland et al. Nature 433, 531 (2005)
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Network properties of bacterial protein-protein interactions
Network of highly conserved
proteins co-occurring in ≥125 genomes
(homologue raw BLAST bit score ≥50).
The most highly conserved proteins
are highly connected, forming a single
interconnected component.
This core set of interactions (including
the ribosome) potentially fulfils critical
roles across all bacteria.
Butland et al. Nature 433, 531 (2005)
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Bioinformatic analyses of interacting protein modules
a Node shading (white to
black) is scaled according
to the increasing number
of genomes in which a
putative interaction is
detected based on gene
co-occurrence using
COGs genomes.
Similar results as for the
highly conserved proteins.
b, Interaction network for proteins with clear co-occurrence (in ≥ 40 genomes).
Proteins with no interacting partner have been removed for clarity.
Butland et al. Nature 433, 531 (2005)
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4 Aim: generate structures of protein complexes
Experiment
Start from 232 purified complexes from TAP strategy.
Select 102 that gave samples most promising for EM from analysis of gels and
protein concentrations.
Take EM images.
Theory
Make list of components.
Bettina Böttcher (EM)
Assign known structures of individual proteins.
Rob Russell (Bioinformatics)
Assign templates of complexes
-If complex structure available for this pair
- if complex structure available for homologous protein
- if complex structure available for structurally similar protein (SCOP)
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How transferable are interactions?
interaction similariy (iRMSD) vs. %
sequence identity for all the available
pairs of interacting domains with
known 3D structure.
Curve shows 80% percentile (i.e. 80%
of the data lies below the curve), and
points below the line (iRMSD = 10 Å)
are similar in interaction.
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Aloy et al. Science, 303, 2026 (2004)
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Bioinformatics Strategy
Illustration of the methods and concepts
used. How predictions are made within
complexes (circles) and between them
(cross-talk). Bottom right shows two
binary interactions combined into a threecomponent model
Aloy et al. Science, 303, 2026 (2004)
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3SOM algorithm:
vector-based circumference superimposition
A 2D variant of the 3D vector-based surface
superimposition that is central to the 3SOM
algorithm. For each tested voxel a on the
circumference of the target, a vector va is
calculated that approximates the normal vector
orthogonal to the tangent line in a and with origin
in a. Vector va is superimposed on each vector vb
that is associated with a voxel b on the
circumference of the template. The goodness-offit of the transformation in question is assessed by
measuring the circumference overlap, the fraction
of target circumference voxels that is projected
onto (or near) the template circumference
(triangles). In 3D, a rotational degree of freedom
is left around the superimposed vectors, which is
sampled in rotational steps of 9°.
Ceulemans, Russell
J. Mol. Biol., 338, 783 (2004)
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Successful models of yeast complexes
(A) Exosome model on PNPase fit into
EM map.
(B) RNA polymerase II with RPB4
(green)/RPB7 (red) built on
Methanococcus jannaschii equivalents,
and SPT5/pol II (cyan) built with IF5A.
(C and D) Views of CCT (gold) and
phosphoducin 2/VID27 (red) fit into EM
map.
(E) Micrograph of POP complex, with
particle types highlighted.
(F) Ski complex built by combination of
two complexes.
Aloy et al. Science, 303, 2026 (2004)
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Cross talk between complexes
(Top) Triangles show
components with at least one
modelable structure and
interaction; squares, structure
only; circles, others.
Lines show predicted
interactions: thick lines imply a
conserved interaction interface;
red, those supported by
experiment.
(Bottom) Expanded view of
cross-talk between transcription
complexes built on by a
combination of two complexes.
Aloy et al. Science, 303, 2026 (2004)
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Summary
A combination of 3D structure and protein-interaction data can already provide a
partial view of complex cellular structures.
The structure-based network derived from cross-talk between complexes
provides a more realistic picture than those derived blindly from interaction data,
because it suggests molecular details for how they are mediated.
Of course, the picture is still far from complete and there are numerous new
challenges.
The structure-based network derived here provides a useful initial framework for
further studies. Its beauty is that the whole is greater than the sum of its parts:
Each new structure can help to understand multiple interactions.
The complex predictions and the associated network will thus improve
exponentially as the numbers of structures and interactions increase,
providing an ever more complete molecular anatomy of the cell.
Aloy et al. Science, 303, 2026 (2004)
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