Cell Signalling Flashcards
Cell Signalling Pathway
- 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
Types of Intercellular signalling
- contact dependent (contact via membrane bound signal/receptor)
- synaptic
- growth factors, hormones, cytokines
2. paracrine (small distance local mediators)
4. endocrine
Cytokines
secreted by immune cells and modulate immune response
Chemokines
subset of cytokines functioning as chemoattractants
Hormones
produced by endocrine glands and distributed by bloodstream
Growth factors
stimulate cell growth/differentiation
Hydrophobic signal molecules
- 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
Signal Integration
- process of responding correctly to a number of different signals
- ie. multiple different signals integrate to provoke a process
Signalling Context
- 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
Receptor State Changes
- 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
Effects of PTMs
- promote/prevent protein binding
- change conformation or activity
- change subcellular localization
- change proteolytic stability
Post Translational Modifications
- 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
Example of PTM
- 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
Protein kinase
- 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
Regulation of Kinases
- 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.
Kinase Inhibitors
- 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
Monomeric GTPases
- molecular switches
- inactive state binds GDP
- GEF promotes GTP exchange
- activate state binds GTP
- GAP promotes hydrolysis of GTP
Signal Specificity
- signalling complexes increase signalling specificity
- assembled on scaffold protein/activated receptor/iner leaflet of lipid bilayer
Multivalency
- increases specificity and affinity of molecular recognition
- linked domains causes high affinity and specificity for tandem phosphorylated motifs
Membrane association
- reduces degrees of freedom for a productive encounter of two molecules
- reduces 3D search to a 2D search
Phase Transitions
- phase transitions are important in multivalent signalling protein assembly
- leads to liquid droplet formation similar to phase separation
Persistence of signal response
transient
- fast turnover of signal mediators
- negative feedback loops
- adaptation
stable
- switch like behaviour
- positive feedback loops
- permanent decisions
Positive feedback
- switch like response
Negative feedback
- reduces signal strength/duration
- inactivates receptor or signal protein
- produces inhibitory protein
- sequesters receptor
- down regulates receptor (lysosome destruction)