The second of 2 summary documents for the biological membranes module, this detailed summary document contains all the key information from 5 weeks of lectures.
The lecture topics covered in this document are as follows:
- Transporters and channels 3
- Tyrosine kinase signalling
- G-proteins
-...
BIOL2210 Weeks 7-11 Revision (Harrison 3 onwards)
Transporters and Channels 3
Ion channels in bacteria & eukaryotes, enable facilitated transport of ions
Some very selective, some only cation selective
Can be non-gated, voltage-gated or ligand-gated (& other types including mechano)
KcsA:
First K+ channel with structure solved & showed how K+ selectivity achieved
P-helix at the top is part of P-segment containing selectivity filter
Top surrounded by amino acid stretch conserved in potassium channels
Bottom half of the cavity is hydrated
Sodium selectivity achieved using
different selectivity filters, but with similar
pore architecture.
- Contains P2 half helix not present
in Kv channels
Note -> Cav & Nav share similarities and
selectivity can be interchanged through
simple mutation in the filter, however
cannot easily distinguish between Cav &
Nav from primary sequence.
Note Nav channel is larger than Kv even though Na<K; this is because Na transported in
partly hydrated form & hydration could change during transport.
Voltage-gated ion channels:
Voltage-gating in Nav channels:
S1-S4 forms voltage-sensing
domain (VSD)
Helix 4 contains positive
residues that respond to
membrane potentials (‘sliding
helix’ model)
S4-S5 linker is mechanical
connection between VSD &
channel.
,27/04/22
Ligand-gated ion channels:
Differences from voltage-gated:
Many channels can sense multiple stimuli
S1-S4 doesn’t move, but S6 still gates opening/closing
Almost all TRP channels are cation selective
Nociceptors = specialised peripheral sensory neurons that detect potentially damaging
stimuli & lead to the sensation of pain.
TRPV1 primary function, responds to noxious temperatures & acidic pH, can lead to
thermal hyperalgesia
An intestinal epithelial cell has plasma membrane organized into 2 regions:
1. Apical = surface that faces outside
2. Basolateral = surface that faces inside
Transcellular glucose transport:
1. Na+/K+ ATPase generates Na+ and K+ conc
gradients
2. Na+ conc gradient & membrane potential
drive uptake of glucose from intestinal
lumen by two-Na+/one-glucose symporter
located in apical surface membrane
3. Glucose enters blood via facilitated
transport catalysed by GLUT2, a glucose
uniporter located in basolateral membrane.
Tyrosine Kinase Signalling
Intracellular signalling is based on chemical principles.
Cells can detect chemical & physical signals
Receptor can convert physical signals into chemical signals
Receptors can act as catalysts and molecular amplifiers
Receptors sense diverse stimuli but initiate limited repertoire of chemical signals
Convergence allows signal integration and coordination; divergence allows multiple
responses to a single signal.
, 27/04/22
Allostery = the ability of a molecule to alter the conformation of a target protein when it
binds non-covalently to that protein.
All RTK proteins have 4 essential components:
1. Extracellular domain containing ligand-binding site
2. Single hydrophobic transmembrane α-helix
3. Cytosolic segment including domain with protein tyrosine kinase activity
4. C-terminal segment containing tyrosine residues that are phosphorylated by own
kinase
RTK signalling suppression:
Receptor-mediated endocytosis followed by receptor degradation in lysosomes is
common method for dampening RTK signal transduction
Treatment of cells with ligand -> less robust response to continuous exposure
o Desensitisation response prevents inappropriately prolonged activity
Non-receptor tyrosine kinases -> signalling mediated by protein-protein interactions
Protein-protein interactions may be mediated by small, conserved domains
Modular interaction domains essential for signal transduction
Sh2 domains = Src homology 2 domains phosphorylated tyrosine residues bind to
proteins with these domains.
Human cells express >100 Sh2 domain-containing proteins
Steps in EGFR signalling:
1. EGF ligand binding
2. Tyrosine phosphorylation (trans-autophosphorylation)
3. Phosphor-EGFR binding to cytosolic proteins
4. Endocytosis
5. Recycling or degradation
RTKs are important drug targets, with drugs falling into 2 categories:
1. Small-molecule inhibitors -> target ATP-binding site of intracellular TKD
2. Monoclonal antibodies -> interfere with RTK activation, destroy RTK-expressing cells
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