Evolution of Protein Interactions in Networks and Complexes

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Evolution of Protein Interactions in Networks and
Complexes
Sarah Teichmann MRC Laboratory of Molecular
Biology Cambridge, UK
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The question How do protein interactions
evolve? networks, complexes, 3D
structures sequence and structure
similarity
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Frequency in protein interaction networks?
?
?
Yeast, yeast-large, fly, worm
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Up to 1/2 interactions in networks1 13
interactions in networks2
1Pereira-Leal, J. Teichmann, S.A. (2005) Genome
Res., 15, 552-559. 2Pereira-Leal, J., Levy,
E.D., Kamp, C. Teichmann, S.A. (2007) Genome
Biol, 8, R51.
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Structures Evolution Assembly in solution
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Echo and Narcissus
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How frequent are homo-oligomers?
60 to 70 of proteins form homo-oligomers
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Selective advantages of homo-oligomers

• Stability of the protein
• Functional advantages

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3Dcomplex.org - a hierarchical classification of
complexes
Levy, E., Pereira-Leal, J., Chothia, C
Teichmann, S.A. (2006) 3DComplex a structural
classification of protein complexes. PLoS Comp
Biol., 2, e155.
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A brief reminder of symmetry
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Evolutionary pathways of complex assembly
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Symmetries found in a non-redundant set of 2500
complexes
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Symmetries found in a non-redundant set of 2500
complexes
Even no. of subunits and gt 4 Cyclic
symmetry 2 Dihedral symmetry 22
When there is a choice, dihedral favoured and
10x more frequent than cyclic
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Evolutionary pathways of complex assembly
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Structures Evolution Assembly in solution
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Conservation of Quaternary Structure - Examples
Where do most protein stand on this spectrum?
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Model of homomer evolution
Constant probability of dimer-, trimerization etc
independent of size of complex
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Homology to the largest interface is common
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An evolutionary relic
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Predictions based on largest interface
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A hypothesis evolution predicts assembly pathway?
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Structures Evolution Assembly in solution
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Macromolecular mass spectrometry (E.B. Erba
C.V. Robinson)
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Complexes with characterised assembly pathways -
agreement with predictions
Observed intermediates or perhaps better
sub-complexes
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Structures 60 to 70 proteins are homomers in
PDB and genomes Evolution Dihedral predominant
over cyclic due to evoln. pathways Assembly in
solution Assembly recapitulates evolution -
large interface intermediates
Interface size and geometry as unifying principle
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Up to 1/2 interactions in networks 13
interactions in networks

• 2/3 of proteins
• Dihedral complex evolution via dimers or cyclic
  w. large interface
• Predict evolution and assembly from interface
  sizes

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Acknowledgements

• Jose B. Pereira-Leal,Gulbenkian Insitute, Lisbon
• Emmanuel D. Levy, MRC-LMB
• Cyrus Chothia, MRC-LMB
• Carol Robinson, Dept Chemistry, Cambridge
• Elisabetta Boeri Erba, Dept Chemistry, Cambridge

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• 60 to 70 proteins are homomers in PDB and
  genomes
• Dihedral predominant over cyclic due to
  evolutionary pathway
• Assembly recapitulates evolution - large
  interface intermediates

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• Duplication of interactions forms up to half of
  all interactions
• Pereira-Leal, J. Teichmann, S.A. (2005) Novel
  specificities emerge by step-wise duplication of
  functional modules. Genome Res., 15, 552-559.

Pereira-Leal, J., Levy, E.D., Kamp, C.
Teichmann, S.A. (2007) Genome Biol, 8, R51.
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Frequency in protein interaction networks?
P
a
r
alogou
s
Dimers
?
yeast (1 011 interactions) yeast-large (15 393)
fly (2 877) worm (2 422)
Pereira-Leal, J., Levy, E.D., Kamp, C.
Teichmann, S.A. (2007) Genome Biol, 8, R51.
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Model of homomer evolution
Constant probability of dimer-, trimerization etc
independent of size of complex
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Obser
v
e
d
0.12
s
P
a
r
alogou
s
Expected
action
Dimers
0.1
r
0.08
action of inte
0.06
0.04
r
f
0.02
0
Y
eas
t
Y
eas
t
-larg
e
Fly
W
or
m
Up to 13 pairwise interactions are between
homologues
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Gene duplication allows asymmetric binding
others CCT proteasome exosome,
spliceosome Photosystem I
Pereira-Leal, J., Levy, E.D., Kamp, C.
Teichmann, S.A. (2007) Genome Biol, 8, R51.
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Conservation of Quaternary Structure
Down to 30 sequence identity, 70 of protein
pairs have their quaternary structure conserved
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Frequency of homology between symmetry types
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A brief reminder about symmetry
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Evolutionary pathways of complex assembly
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Subunit arrangement

• Homo-oligomers are made of repetitions of the
  same protein and can form

Open complexes (may form filaments)
Closed complexes (may not form filaments)
This type of complex can be deleterious for an
organism (Sickle cell anemia, Huntingdon, Parkinso
n, Alzheimer)
Majority of complexes
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Representing complexes in a simple form that
summarizes key features, and allows comparison
Process inter-sub-units contacts Detect
identical chains Detect structural homologies
(Using the SCOP classification)
Nodes are polypeptide chains Edges are
interfaces between chains Same color - same
gene Same shape - homologous gene
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Convert all atomic structures into
graphs,compare and group similar graphs
20875 structures (including monomers)
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3Dcomplex.org - the hierarchical classification
Levy al, Plos Comp. Bio. 2006
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An evolutionary relic