Introduction to biological networks

1
Introduction to biological networks
2
(No Transcript)
3
Types of biological network

• Genetic regulatory network
• Protein-protein interaction network
• Metabolic network
• Signal transduction network

4
Gene Regulation Network
Regulatory proteins
Promoter 1
Promoter 3
Promoter 2
5
Transcription network
activator
repressor
6
Protein-Protein Interaction Network
Saccharomyces cerevisiae
Node protein Edge protein-protein interaction
7
Metabolic Network
Metabolic Pathway
Node Chemicals or Proteins Edge
Chemical reaction
8
cAMP signaling transduction of Dictyostelium
discoideum
Dictyostelium discoideum
9
High throughput experiments to identify
interaction in network
10
Experiments for Protein-Protein Interaction
11
Saccharomyces Cerevisiae
Nature, 415, 180, (2001)
Nature, 415, 141, (2001)
HMS-PCI
TAP tag
Cellzome is a private Corporation in German
12
Helicobacter Pylori
13
Drosophila melanogaster
Two hybrid
Science, 5 Dec, 302, 1727, (2003)
14
Caenorhabditis elegans (Worm)
15
Experimetal Methods

• HMS-PCI(High-throughput mass spectrometric
  protein complex identification)
• TAP (Tandem Affinity Purification)
• Yeast two hybrid
• Immunoprecipitation
• Phage display
• Fluorescence resonance energy transfer (FRET)

16
TAP tag
TAP tag Purification

• TAP tag contains
• 1. two IgG binding domains of Staphylococcus
  aureus protein A (ProtA)
• 2. Calmodulin binding petide (CBP)
• 3. TEV protease cleavage site

17
(No Transcript)
18
TAP tag
19

• Advantage
• Detects in physiological condition,
  high-throughput
• Disavantage
• Tag may disturb protein interaction
• miss the protein complexes that are not
  present in such condition

20
HMS-PCI

• High-throughput mass spectrometric protein
  complex indentification
• Use epitope tag

21
Yeast Two Hybrid Method
22

• Advantage
• In vivo experiment, transient and unstable
  interactions could be detected
• Disadvantage
• many false positive, only two proteins were
  detected at a time
• it take place in the nucleus, so many protein
  interactions are not detected in their native
  environment

23
Immunoprecipitation
24

• Advantages of this approach
• This approach can test  the protein
  associations in nature condition in the cell.
• The isolated proteins (or complex) can be used
  to do other functional assay.

25
Phage Display
26

• Advanage
• high throughput
• Can be used to elucidate nuclear protein
  interaction.

27
Fluorescence Resonance Energy Transfer (FRET)
When the donor and acceptor come close to 10100
, the donor will transmit energy to acceptor,
we could monotor the protein interaction by
fluorescence.
28
Protein-Protein Interaction Database

• BIND Biomolecular Interaction Network Database
• http//www.blueprint.org/bind/bind.php
• DIP Database of Interacting Protein
• Genome Website
• http//www.hgmp.mrc.ac.uk/GenomeWeb/

29
(No Transcript)
30
(No Transcript)
31
Yeast protein-protein interaction

• ?About 80000 interactions between yeast proteins
  are available from high-throughput methods.
• ?Only 2400 interactions are supported by more
  than two methods.
• ?Possible reasons are
• the methods may not have reached saturation
• many methods may produce false positives
• some methods has difficulties for certain
  types of interaction.

32
Assign 80000 interactions of 5400 yeast proteins
a confidence value
11855 interactions with high and medium
confidence among 2617 proteins
33
Biological significance of protein-protein
interaction?

• Assemble proteins together into protein complex
• Bring the proteins(signaling proteins) to its
  activate or function place
• Binding of one protein to another can induce
  conformational change that affect activity or
  accessibility of additional binding domain

34
Mad
Myc
Max
Burkitt lymphoma neuroblastomas small cell lung
cancers
Promoter
Gene Sequence
35
Partner Specific
Cdc28 YBR160W
Cdc28 YBR160W
Yeast cell cylce Cyclin-CDK (Cyclin-dependent
kinases) complexes
36
Scaffold Protein
Reactants
E1
E2
Product
E3
Reactants
E1
E2
E3
Scaffold
Reactants
E1
E2
Protein complex
Product
E3
37
Experiments for genetic regulation interaction
38
Protein-DNA interaction
Chromatin Inmmunoprecipitation (ChIP)
39
Science 298, 799, (2002).
40
Yeast cell cycle regulatory network
41
Mathematical modeling of biological networks as a
graph
42
Protein-protein interaction network
43
Protein-protein interaction network
Node protein Edge interaction
44
Protein-Protein Interaction Network
Saccharomyces cerevisiae
Node protein Edge protein-protein interaction
45
Metabolic network
Substrates linked to all its products
Node protein or chemicals Edge chemical reaction
46
Biochemical reduction
Reduced graph representation
Graph representation
Pathway map
47
E. coli metabolic network with biochemical
reduction
48
Topological reduction
Remove hair nodes, and replacing arc with single
link
49
E. coli metabolic network with topological
reduction
50
Both protein-protein interaction network and
metabolic network are modeling as undirected
graphs.
51
Adjacency Matrix

• Aij 1 if ith protein interacts with jth
  protein
• Aij0 otherwise
• AijAji (undirected graph)
• Aij is a sparse matrix, most elements of Aij are
  zero

52
Gene Regulation Network
Regulatory proteins
Promoter 1
Promoter 3
Promoter 2
53
Control element I
Transcriptional Control
Transcription factors
activator
repressor
Gene A
54
Control element II
Protein-Protein Interaction kinase and
phosphatase

• On-off switch
• Multiple sites
• Location control (nuclear entry)
• Tags for degradation
• Signal transduction

55
Protein interactions
protein-protein binding

• On-off switching upon binding
• Partner-specific

Cdc28
Cdc28
56
Integrated genetic network
A
B
A activates B A inhibits C A is the activator of
B A is the inhibitor of C
C
57
Integrated genetic network
A
B
A activates B A inhibits C A is the activator of
B A is the inhibitor of C
C
58
(No Transcript)
59
Integrated genetic network
Green arrow activate interaction Red arrow
inhibitive interaction
60
Adjacency Matrix

• Aij 1 for activated interaction (green
  arrow)
• Aij-1 for inhibitive interaction (red arrow)
• Aij ?Aij (directed graph)
• Aij0 otherwise

61
? ? ? ?

• Write down the adjacency matrix for the following
  graph.