Cellular Design Prinicples

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Cellular Design Prinicples

• Why was it made that way??
• What performance objectives are met by particular
  designs?

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Cellular Design Prinicples

• Regulated Recruitment

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How to impose specificity on enzymes?

• Strategy A lock and key interaction between
  enzyme and substrate
  
• Only lactose fits into and is cleaved by
  ?-galactosidase even closely related sugars
  arent
  
• Strategy B Regulated Recruitment

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Regulated Recruitment

• Adhesive interactions bring the E S together
• The adhesive regions are usually well-separated
  from the active site of the enzyme and from the
  part of the target substrate that is to be
  modified
• The active site may actually have a relatively
  weak specificity
  
• Mark Ptashne and Alex Gann
• 1998, Current Biology, 8R812R822
• 2002, Genes Signals, Cold Spring Harbor Press

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Regulated Recruitment

• Many transcription factors have two adhesive
  regions, one of which binds to DNA and the other
  to RNA polymerase
  
• As a result, the polymerase (Enzyme) is recruited
  to a gene (Substrate)
  

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Weak binding may be advantageous
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Kinase-substrate docking interaction
A "double selection" for fidelity
Kinase
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1
Substrate
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Mating
Stress Response
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The basic idea
Recruiter
Enzyme
Active site
Target site(s)
Substrate
Recruiter
Enzyme
Recruiter
Substrate
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The basic idea
Recruiter
Enzyme
2
1
Substrate
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Interactions
Recruiter
Enzyme
2
1
Recruiter
Substrate
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Cellular Design Prinicples

• Regulated Recruitment
• Evolvability

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Evolvability

• a.k.a. evolutionary adaptability
• The capacity of a lineage to evolve
• An organisms capacity to generate heritable,
  selectable phenotypic variation.
  
• Kirschner Gerhart 1998 PNAS 958420

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Not very evolvable
Evolvability

• If a lot of mutations are needed to produce a
  novel trait or function

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Example not very evolvable
Evolvability
Conventional allostery
Dueber et al 2004 Curr. Opin. Structural Biol.
14690
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Example evolvable
Evolvability
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Modular allostery involves activation by double
inhibition, which is generally more evolvable
than activation by a stimulatory change, because
its easier to inhibit a protein (or a domain)
than to induce a stimulatory conformational
change.
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P
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P
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P
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Conserved Core Processes

• Replication
• Transcription
• Translation
• Metabolism
• Conserved in all life forms

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Conserved Core Processes

• Cytoskeleton - actin, tubulin, etc
• Cell cycle using cyclins/CDKs
• Many signaling pathways
• Protein sorting
• Conserved in all eukaryotes

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Conserved Core Processes

• WHY? - Hypothesis
• Optimum solution
• Frozen accident

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Optimum Solution

• If something is the best possible solution, it
  will be highly conserved due to positive
  selection
  

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Frozen Accident

• Natural selection works with the best available
  at the time, not the best possible
  
• hammer a nail with a wrench
• This sub-optimal solution gets embedded in other
  systems and is constrained to change

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Constrained because of embededness

• The genetic code

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Constrained because of embededness

• Actin - 91 identical yeast to human
• Tubulin - 86
• Engaged in numerous functional interactions at
  sites covering most of the protein surface

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Deconstraint

• Certain rocesses can be deconstraining because
  they reduce the interdependence of components
  
• They make it easy for new functions to evolve

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Deconstraint Mechanisms

• Flexible versatile regulators
• Calmodulin, a sticky clamp
• kinases
• Weak Linkage
• Exploratory Mechanims
• Microtuble dynamic instability (show movie)
• Angiogenesis

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Cellular Design Prinicples

• Regulated Recruitment
• Evolvability
• The road matters

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Mating
Stress Response
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A
B
A'
B'
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Signal Identity
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Evolution of signaling networks
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Can respond to more signals
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Can respond more comprehensively
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