Protein Trafficking

trafficking

a system of addresses and carriers that ensure delivery of cargo to the right place

forms of intracellular trafficking

gated

transmembrane

vesicular

can be unidirectional or bidirectional

single peptide proteins

inserted into the ER through a membrane translocation

proteins with transmembrane domain

released into the ER membrane through a lateral translocon gate

enable communication across a membrane

vesicular transport

cargo is transported between compartments in vesicle pachages that bud and fuse

coat proteins mediate vesicle formation

• recruit cargo via receptors

• bend membranes to form vesicles

• different coats for different vesicles

vesicles guided to target membranes by RAB proteins where SNARE proteins enable fusion

from ER to Golgi

ER chaperones assist protien folding

proteins are transported to the GOlgi for modification and sorting

ER resident proteins have retention signals

proteins that are leaving have exit signals - must be properly folded, quality control - improperly folded proteins are degraded

cystic fibrosis

• change in F508 in CFTR chloride channel

• folding defect prevents ER exit, channel can’t reach the plasma membrane

• reduced Cl- transport results in thick mucus in lungs, overgrowth of bacteria

oligosaccharide processing and sorting

happens in Golgi

ordered series of compartments

biochemical/functional modifications

cargo sorting

Golgi to Lysosome

Lysosome - intracellular digestion/catabolism compartment

• acid hydrolases: enzymes that use water to break a chemical bond, work best in acidic environment

• low luminal pH achieved by proton pumping

transport of hydrolytic enzymes to lysosome

requires mannose 6-phosphate

activity restricted to lysosome by - M6P sorting signal, decreased pH required for activity

lysosomal storage disorders

Mutations disrupting the targeting or activity of lysosomal hydrolases or transport of enzymes

often (not exclusively) impacts the CNS

exocytosis

from the trans Golgi to the cell exterior

Constitutive secretion - continuous traffic to the plasma membrane or beyond as cargo is synthesized

regulated secretion - signal mediated plasma membrane fusion

synaptic transmission

requires regulated exocytosis

communication between neurons or neurons and muscle cells

Botulism - toxin cleaves SNAREs at neuromuscular junction preventing release of acetylcholine → flaccid paralysis

endocytosis

receptor mediated - uptake of specific macromolecules from the extracellular space, requires receptors, receptors recycled to cell surface

phagocytosis - uptake of large particles such as bacteria, macrophages, neutrophils, dendritic cells

rapid vesicle recycling

required to sustain synaptic transmission

exercise induced collapse in labs

• flaccid paralysis

• point mutation that slows dynamin-1 activity

• vesicle recycling can’t keep up during periods of high activity