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Protein sorting and trafficking (protein traffic (cargo selection (active…
Protein sorting and trafficking
protein traffic
vesicle fusion
rab proteins
give molecular identity to vesicle --> only if this identigy correlates with identity of acceptor then vesicle can bud
snare proteins
molecule identity
drives fusion process
snare pairing brings 2 membranes close together
water squeezed out
stalk and hemifusion intermediates
mechanism
1) vesicle buds from donor compartments
vesicle pinches off and translocates from donor to acceptor compartment
vesicle docks with acceptor compartment
vesicle fuses with acceptor compartment releasing contents into lumen
directionalitya
retrograde (backward)
antrograde (forward)
cargo selection
selective exclusion
proteins that mis-fold in the ER
antibodies are not packaged into buds they are correctly assembled
ER = quality control station in secretory pathway
active recruitment
some proteins will have domains that will interact with coat proteins
proteins may interact with cargo receptors spanning the membrane
passive inclusion
proteins can passively be included in the bud (may have to be returned to ER)
retrograde transport
ER resident proteins have KDEL sequence which can be recognised by KDEL receptors
ER resident proteins are translocated back to ER by COPI vesicles
KDEL receptors are transported back by COPII vesicles
mitochondrial targeting
general information
always at N terminus
varies in size from 20 to 80 amino acids8
multiple positively charged amino acids make an amphipathic a helix
mechanism
translocation accross membranes requires membrane potential (negative in matrix)
protein has to pass through 2 membranes
TOM = translocator of the outer membrae
TIM = translocator of the inner membrane
the binding sequence binds to receptors on the outer membrane
energy from ATP hydrolysis is required
chaperones use ATP to release protein
nuclear targeting
proteins that contain long strethces of positively charged (in neutral pH) amino acids are important in nuclear targeting)
called nuclear localisation signal
stretches are located on the surface of the protein
lysine
arginine
nuclear pore complex
components
lumenal subunit
annular subunit
cytosolic fibril
nuclear fibril
nuclear basket
column subunit
contains nuclear import receptors
transport is said to be active as it is directional and requires energy
bind to nuclear localisation signals complex of NLS and NIR bind to cytosolic fibrils
Mechanism
nuclear import receptor bind to NLS which bind to cytosolic fibrils and complex is transported to pore
import is of fully synthesised and fully folded protein
powered by GTP hydrolysis
NIR bound to cargo enters nucleus
Ran-GEF causes Ran-GDP to change into Ran-GTP --> Ran-GTP binds to nuclear import receptor
release of cargo
ran-GTP can move NIR out of nucleus
in cytoplasm: ran-GAP hydrolyses GTP to GDP --> low affinity for nuclear import receptor --> release
nuclear import receptor ready to bind to NLS
Endoplasmic reticulum targeting
general information
positively charged terminus
hydrophobic stretch of amino acids
often at N terminus
8-15 amino acids in lengths
mechanism
important
translocation starts in cytosol but once signal sequence emerges then transferred to ER then finishes translocation
for transmembrane proteins
signal sequence not cleaved remains transmembrane
signal sequence is called anchor sequence
no signal peptidase cleavage sequence
have longer hydrophobic sequence
for lumenal proteins
signal sequence is cleaved by lumenally located signal peptidase complex
signal sequence emerges from ribosome
binds to signal recogntion particle
translation of protein stops
protein can bind to ER membrane which contains SRP receptor
SRP receptor brings protein to translocon
SRP receptor and SRP hydrolyse their respective GTP
GTP hydroylsis changes conformation --> SRP released from chain and recycled
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