Types of proteinprotein interactions PPI

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Types of protein-protein interactions (PPI)
Non-obligate PPI
Obligate PPI the protomers are not found as
stable structures on their own in vivo
Non-obligate homodimer Sperm lysin
Obligate homodimer P22 Arc repressor DNA-binding
Obligate heterodimer Human cathepsin D
Non-obligate heterodimer RhoA and RhoGAP
signalling complex
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Types of protein-protein interactions (PPI)
Non-obligate PPI
Obligate PPI usually permanent the protomers
are not found as stable structures on their own
in vivo
Permanent (many enzyme-inhibitor
complexes) dissociation constant KdAB / AB
10-7 10-13 M
Transient
Weak (electron transport complexes) Kd mM-?M
Non-obligate transient homodimer, Sperm lysin
(interaction is broken and formed continuously)
Intermediate (antibody-antigen,
TCR-MHC-peptide, signal transduction PPI), Kd
?M-nM
Strong (require a molecular trigger to shift the
oligomeric equilibrium) Kd nM-fM
Obligate heterodimer Human cathepsin D
Non-obligate permanent heterodimer Thrombin and
rodniin inhibitor
Bovine G protein dissociates into G? and G??
subunits upon GTP, but forms a stable trimer upon
GDP
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Types of protein-protein interactions (PPI)
Non-obligate PPI
Obligate PPI usually permanent the protomers
are not found as stable structures on their own
in vivo
Permanent (many enzyme-inhibitor
complexes) dissociation constant KdAB / AB
10-7 10-13 M
Transient
Weak (electron transport complexes) Kd mM-?M
Non-obligate transient homodimer, Sperm lysin
(interaction is broken and formed continuously)
Intermediate (antibody-antigen,
TCR-MHC-peptide, signal transduction PPI), Kd
?M-nM
Strong (require a molecular trigger to shift the
oligomeric equilibrium) Kd nM-fM
Obligate heterodimer Human cathepsin D
Non-obligate permanent heterodimer Thrombin and
rodniin inhibitor
Bovine G protein dissociates into G? and G??
subunits upon GTP, but forms a stable trimer upon
GDP
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Structural characteristics of protein-protein
interfaces
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Types of protein-protein interactions (PPI)
Non-obligate PPI
Obligate PPI usually permanent the protomers
are not found as stable structures on their own
in vivo
Permanent (many enzyme-inhibitor
complexes) dissociation constant KdAB / AB
10-7 10-13 M
Transient
Weak (electron transport complexes) Kd mM-?M
Non-obligate transient homodimer, Sperm lysin
(interaction is broken and formed continuously)
Intermediate (antibody-antigen,
TCR-MHC-peptide, signal transduction PPI), Kd
?M-nM
Strong (require a molecular trigger to shift the
oligomeric equilibrium) Kd nM-fM
Obligate heterodimer Human cathepsin D
Non-obligate permanent heterodimer Thrombin and
rodniin inhibitor
Bovine G protein dissociates into G? and G??
subunits upon GTP, but forms a stable trimer upon
GDP
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The conclusion is disappointed

• The problem in definition and study of transient
  protein complexes
• some of them (weak) show an elevated
  monomer-dimer equilibrium, some (strong) do not
  necessarily change their oligomeric state
  continuously and become effectively permanent
  upon co-operative binding to a macromolecule (for
  example, DNA)
• they often dont form stable crystals nor give
  good NMR data
• since they have interfaces similar to crystal
  contacts, it may be difficult to derive the true
  biological structure of the complex from the
  crystal structure.
• It is difficult to discriminate between different
  types of PPIs based on physicochemical and
  geometrical interface properties.
• The evolution of PPIs is still far from
  understood.
• The functional relevance of weak PPI is often
  unclear, especially for homo-oligomers.

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Result 1. Significance of oligomerisation. Some
examples
1. Local or temporary oligomerisation can
establish a concentration gradient and facilitate
the receptor binding process. For example, IL8,
SDF1?, MCP-1 (see Table 1, p.993). 2. Local or
temporary oligomerisation can provide temporary
storage of protein. For example, storage of CNTF
in the peripheral nerve (see Table 1 ,
p.993). 3. Biological function or activity can
be modulated by oligomerisation. For diverse homo
and hetero-dimerisation between five members of
the Rel/NFkB family, with varying affinities,
regulate different genes (see Table 1 ,
p.993). 4. The monomer-dimer transition can
provide a dynamic trigger inducing allosteric
conformational changes in the near environment.
For example, lysin (see Table 1 , p.994),
possibly, SCF (see Table 1 , p.993).
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Weak transient homodimers
Transient heterodimers
1. Curation of significance of oligomerisation
Yes Yes
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• Physicochemical and geometrical properties of the
  oligomeric interfaces were obtained using an EBI
  program PROFACE
• (Jones Thornton, PNAS USA, 1996)
• Interface atoms are defined as atoms that lose
  more than 0.01 ?2 upon complexation.
• Measure of contact area. The change in accessible
  surface area upon complexation is measured as the
  average difference between ASA of both protomers
  on their own and in complex.
• Measure of the hydrophobicity of the complex. The
  polarity is measured as the percentage of the
  contact area that involves polar atoms.
• Measure of the interface shape. The planarity of
  the interface is measured as rmsd of the
  interface atoms from the least squares plane
  fitted through the interface atoms. (A high rmsd
  denotes a rough or bent interface.)
• Measure of the shapes complementarities of the
  interface. GAP index is measured as volume of the
  gaps existing between the protomers .
• Measure of the strength of the contact. Pair
  score (for homodimers only, Table 3) is a
  statistical potential based on atom-pair
  frequencies across the interfaces of homodimers.
  A low log-odds score corresponds with a high
  probability to form a dimer.

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Is there linear correlation between affinity and
contact area size for transient dimers?
Low affinity
High affinity
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Result 2
Weak transient homodimers
Transient heterodimers
1. Curation of significance of oligomerisation
Yes Yes
2. Show linear correlation between affinity and
contact area size
No Yes
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Structural characteristics of protein-protein
interfaces weak transient homodimers can be
distinguished from the more stable dimers
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Structural characteristics of protein-protein
interfaces non-obligate heterodimers can not be
distinguished from the more stable obligate
complexes
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Result 3
Weak transient homodimers
Transient heterodimers
1. Curation of significance of oligomerisation
Yes Yes
2. Show linear correlation between affinity and
contact area size
No Yes
3. Can be distinguished from the more stable
obligate dimers by contact area and polarity?
Yes No (Yes for only antigen-antibody
complexes)
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• Sequence homologues (E-value by Psi-Blast 10-15)
  have been identified for the set 1 of weak
  transient homodimers (Table 5).
• The sum-of-pairs matrix conservation scores of
  residues comprising the inner interface (that
  have less than 5 of their ASA exposed to the
  solvent in the complex), the total interface
  (that lose more than 1 ?2 upon complexation), and
  all the surface residues have been determined by
  the multiple sequence alignment of the Psi-Blast.
  Score ranges from 0 to 1. A value of 0 indicates
  the position is not conserved a value of 1
  indicates it is highly conserved. The ratio (last
  column, Table 5) is greater than 1.0 suggests a
  possible functional evolutionary restraint for
  homo-dimerisation.
• The average ratio mean conservation inner
  interface / surface for 14 transient weak
  homodimers was 1.10.

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Result 4
Weak transient homodimers
Transient heterodimers
1. Curation of significance of oligomerisation
Yes -
Yes Yes
2. Show linear correlation between affinity and
contact area size
No Yes
3. Can be distinguished from the more stable
obligate dimers by contact area and polarity?
Yes No (Yes for only antigen-antibody
complexes)
4. Interface residues are more conserved than
surface residues for a conserved oligomeric state
Yes -
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• Structural homologues (same SCOP family, i.e.
  same homologues CATH superfamily) have been
  identified for the set 1 of weak transient
  homodimers.
• The result 9 proteins families amongst 13
  studied families of weak transient homodimers
  (Figure 5) form dimers, i.e. the quaternary state
  is conserved throughout the superfamily. Within
  families of IL-8-like chemokines, insulin,
  retinol-binding proteins, and galectin homologues
  with higher order oligomeric states (i.e. trime,
  tetramer, hexamer) are found.
• For each protein and species entry in the SCOP
  family, a representative structure was selected
  and analyzed for its interface characteristics
  (Figure 5).
• The result The lower and upper boundaries of
  contact area size and pair score potential (A
  measure of the strength of the contact. A low
  log-odds score corresponds with a high
  probability to form a dimer.) for 13 studied
  families of homologues are those found for the
  validated set of weak transient homodimers with
  exception for 4 homodimers (Figure 5) which are
  more stable than others.

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Result 5
Weak transient homodimers
Transient heterodimers
1. Curation of significance of oligomerisation
Yes -
Yes Yes
2. Show linear correlation between affinity and
contact area size
No Yes
3. Can be distinguished from the more stable
obligate dimers by contact area and polarity?
Yes No (Yes for antigen-antibody
complexes only)
4. Interface residues are more conserved than
surface residues for a conserved oligomeric state
Yes -
5. Existing structural homologues demonstrate the
same range of ASA and pair scores as proteins
from the set of weak homodimers
Yes -