1
Q
Cell Signalling Pathway
A
- extracellular signal molecule
- receptor protein activation (conformational change in receptor)
- intracellular signalling proteins for signal transduction downstream
- effector proteins
- altered gene expression/metabolism/cell shape
2
Q
Types of Intercellular signalling
A
- contact dependent (contact via membrane bound signal/receptor)
- synaptic
- growth factors, hormones, cytokines
2. paracrine (small distance local mediators)
4. endocrine
3
Q
Cytokines
A
secreted by immune cells and modulate immune response
4
Q
Chemokines
A
subset of cytokines functioning as chemoattractants
5
Q
Hormones
A
produced by endocrine glands and distributed by bloodstream
6
Q
Growth factors
A
stimulate cell growth/differentiation
7
Q
Hydrophobic signal molecules
A
- cross plasma membrane directly
- mainly steroids or sex hormones
- once activated by hormone binding, nuclear receptors translocate to the nucleus and bind to DNA to regulate gene expression
8
Q
Signal Integration
A
- process of responding correctly to a number of different signals
- ie. multiple different signals integrate to provoke a process
9
Q
Signalling Context
A
- same signal molecule elicits different response
- context dependent
- acetylcholine can bind to heart pacemaker cells to decrease firing, salivary gland cells to secrete enzymes, and skeletal muscle cells to stimulate contraction
10
Q
Receptor State Changes
A
- conformational changes in proteins link signal inputs to outputs
- can cause PTMs, complex formation/dissociation, changes in localisation within cells
- inputs can change the protein at each signalling ‘node’ from off to on
11
Q
Effects of PTMs
A
- promote/prevent protein binding
- change conformation or activity
- change subcellular localization
- change proteolytic stability
12
Q
Post Translational Modifications
A
- writer: addition of modification
- reader: protein binding to PTM to carry on signal
- eraser: eraser of modification
- eg. phosphorylation of tyr, ser, threonine
- readers bind to phos. residue to mediate signalling and lead to output
13
Q
Example of PTM
A
- tyrosine kinase/phosphatase with SH2 domain
- receptor signalling - histone acetyl transferase/deacetylase with bromo domain
- increased transcription - ubiquitin ligase/deubiquitinase with UIM domain
- DNA damage response
14
Q
Protein kinase
A
- human kinome is 500 kinases (400 ser/threonine)
- conserved structure:
- N lobe and C lobe
- ATP substrate binding pocket in cleft
- gamma P of ATP transferred to protein
15
Q
Regulation of Kinases
A
- regulation by conformational changes and phosphorylation of activation loop
Inactive: - C helix in up conformation
- Lys-Gly salt bridge not formed
- activation loop blocks ATP binding site for autoinhibition
Active: - C helix in down conformation
- salt bridge formed
- activation loop moves out of ATP binding site and is phos.
16
Q
Kinase Inhibitors
A
- many cancer drugs target kinases
- eg. Imatinib is an ATP competitive inhibitor targeting the Bcr-Abl fusion protein encoded by the Philadelphia chromosome (Abl is tyrosine kinase)
- treats chronic myelogenous leukemia
17
Q
Monomeric GTPases
A
- molecular switches
- inactive state binds GDP
- GEF promotes GTP exchange
- activate state binds GTP
- GAP promotes hydrolysis of GTP
18
Q
Signal Specificity
A
- signalling complexes increase signalling specificity
- assembled on scaffold protein/activated receptor/iner leaflet of lipid bilayer
19
Q
Multivalency
A
- increases specificity and affinity of molecular recognition
- linked domains causes high affinity and specificity for tandem phosphorylated motifs
20
Q
Membrane association
A
- reduces degrees of freedom for a productive encounter of two molecules
- reduces 3D search to a 2D search
21
Q
Phase Transitions
A
- phase transitions are important in multivalent signalling protein assembly
- leads to liquid droplet formation similar to phase separation
22
Q
Persistence of signal response
A
transient
- fast turnover of signal mediators
- negative feedback loops
- adaptation
stable
- switch like behaviour
- positive feedback loops
- permanent decisions
23
Q
Positive feedback
A
- switch like response
24
Q
Negative feedback
A
- reduces signal strength/duration
- inactivates receptor or signal protein
- produces inhibitory protein
- sequesters receptor
- down regulates receptor (lysosome destruction)
25
Oscillation
- negative feedback with delay causes signal oscillations
- most biological loops have built in delay as it takes time to add PTMs or convey the downstream signal
- damped oscillations: minimal oscillation
- robust oscillations: neg. feedback + delay + pos. feedback
- additional pos. feedback makes system bistable
- oscillators depend on instability of a component in the negative feedback loop
- when all components are stable, the output peaks once and then decays into a steady inhibited state (transient)
26
Xenopus oocyte cell cycle
- robust natural oscillator
Core negative feedback loop:
The CDK-cyclin complex phosphorylates the anaphase-promoting complex (APC), which promotes Cdc20 binding. The APC-Cdc20 complex polyubiquitylates the cyclin, targeting it for destruction.
Positive feedback loop 1:
The CDK-cyclin complex phosphorylates the kinase Wee1, thereby inactivating it; Wee1 phosphorylates the CDK-cyclin complex, thereby inhibiting it (double negative loop).
Positive feedback loop 2:
The CDK-cyclin complex phosphorylates the phosphatase Cdc25, thereby activating it; Cdc25 dephosphorylates the CDK-cyclin complex, thereby activating it (double positive loop).
27
Logic Gates
- AND: both signals needed for output
- NOR: neither signal needed for output
- OR: either both or just one needed for output
- XOR: either one or the other (not both) needed for output
28
Sustained Input Detector
- combining feedforward loop with an AND gate
- achieve a transient input doesn't lead to output
- you want a sustained input to lead to output
- fast branch into gate (eg. phos)
- slow branch (eg. gene expression changes)
- both need to occur
- if just a blip of signal the lack of slow branch will cause no response
- if coincident signals are detected with sustained response, both branches are on to produce a output
29
Mitogen Signalling
example of sustained input detection
- mitogen is a growth signal for division
- need long presence of mitogen
- activates MAP kinase that phosphorylates TF (slow path)
- TF transcribe FOS1 protein
- FOS1 is unstable and needs phos. to result in division
- fast pathway is this stabilisation
- MAP kinase must stay activated long enough to phos. FOS1
ICB
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