Bioregulatory networks

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Bioregulatory networks

• Molecular Interaction Maps
• Network structure function
• Simulation

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Problem How to represent the molecular
interactions that constitute bioregulatory
networks in a graphical manner akin to circuit
diagrams.
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Bioregulatory network features Multi-protein
complexes Protein modifications (e.g.
phosphorylations) Interactions of protein
domains Actions (e.g. reversible binding,
enzymatic catalysis) Contingencies (e.g.
stimulation / inhibition) Localization /
translocation (e.g. membrane, nucleus) Gene
expression
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Some difficulties specific to bioregulatory
networks Multi-molecular complexes. Covalent
modification (e.g. phosphorylation).
Contingencies. Interactions of protein
domains.
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Some desirable features of diagrams Avoid
ambiguity (but tolerate it when it is
unavoidable) Where is it in the
diagram? (molecular species only in one place)
Access to salient facts and references
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Multi-protein complexes
x
x A B
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Protein modification (e.g., phosphorylation)
x
x phosphorylated A
P
Phosphorylation of A blocks the kinase activity
of A.
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Phosphorylated A phosphorylates B
P
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Assembly of a multimolecular complex ORC, the
origin replication complex (from a map by Mirit
Aladjem)
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Translocation
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slow
slow
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The kinase activity of Cdk2 requires binding to
Cyclin E AND phosphorylation at T160, but is
inhibited by phosphorylation at T14/Y15.
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The state-combination line
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Action in trans
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Cleaving a protein
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Actions on gene promoters
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The SH3 domain binds intra-molecularly to the Pro
domain.
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The Src tail region can be phosphorylated at Tyr
527.
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The SH2 domain binds to the tyrosine-phosphorylate
d tail.
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The 2 intra-molecular bonds form cooperatively,
and fold the Src molecule, hiding the kinase
domain and keeping Src in an inactive
configuration.
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A myristyl group is bound to the N-terminus of
Src.
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Myristoylated Src binds to plasma membrane.
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However, access to Tyr416 is blocked by the
intra-molecular folding.
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When EGFR is activated, several of its tyrosines
are phosphorylated.
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Through one of its phosphotyrosines, activated
EGFR recruits p85.
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Pro domain of p85 competes with Pro of Src for
binding to SH3 of Src
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Phosphotyrosine of EGFR competes with P-Tyr527
for SH2 of Src
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Then a phosphatase can remove Tyr527 . . .
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