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MM9 - Dynamic Regulation of Protein (ii) (Ubiquitin-Proteasome System…
MM9 - Dynamic Regulation of Protein (ii)
Ubiquitin-Proteasome System (UPS)
ubiquitin
tag for degradation
signals destruction
small highly conserved compact protein
added to lysine residues on protein, then more join to form poly-ubiquitin chain
continuously recycled
protein stability determined by its ability to be ubiquitinated
proteasome
recognises poly-ubiquitin chain
large multi-subunit protein
barrel shaped
7 alpha type proteins @ ends of barrel
7 beta-type proteins in 2 central beta rings
cleave targeted proteins @ different locations
trypsin cleaves after arginine/lysine
chymotrypsin cleaves after aromatic AAs (tyrosine/phenylalanine
caspase-like cleaves after aspartic/glutamic acid
targeted proteins enter through opening @ top, peptides exit @ bottom
in nucleus or cytosol
all subtypes have same composition as they all have the same function
degrades target proteins to short peptides
19S subunit (cap complex) regulates ubiquitin accessibility to proteasome
protein brought to 20S subunit to be degraded (ATP needed for unfolding of primary structure)
ubiquitination = multistep process...
1) ubiquitin activated via ubiquitin-activating enzyme E1 (uses ATP)
2) ubiquitin transferred to ubiquitin-conjugating enzyme E2
3) ubiquitin transferred to target protein via E3 ligase
4) E3 recognises target protein
adds specificity + complexity
mono, multi + polyubiquitinated proteins can be degraded lysosomally
only poly-ubiquitinated proteins proteins can be degraded proteolytically (chain needed
E3 ligases + disease
Parkinson's
loss of function mutation in Parkin E3 residue
parkin over expression protects against toxins
AR, early onset
loss of ligase activity
also plays role in sporadic cases
Tumorigenesis
MDM2 = E3 ligase that inhibits + degrades tumour suppressor P53
increased MDM2 in many cancers
UPS inhibitors
used to treat multiple myeloma (cancer of plasma cells)
e.g. Bortezomib
NF-kappa-beta
TF, NB in regulating cell proliferation
turned on by degradation of inhibitor kappa-beta
cancer treatment: block inhibitor-kappa-beta degradation, stops cell proliferation