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lys
Two strategies for protein degradationTwo strategies for protein degradation
1) Send the protein to a degradative compartment
2) selective degradation of individual molecules
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Cellular protein degradationCellular protein degradation
highly processive
protein 5-8 a.a.
extremely specificsame cellular compartment, half life can vary from 2 min to many days
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“an old hammer is made from two heads and three handles…”
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Protein steady state kineticsProtein steady state kinetics
the steady state can be due to high or low k’sthe steady state can be due to high or low k’s
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Protein steady state Protein steady state in vivoin vivo
protein
synthesis degradation
to change the concentration of a protein the cell can alter either process
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COO-+H3N COO-
COO -
Proteases are well known enzymes…Proteases are well known enzymes…
COO -
+H3N
COO -
+H3N
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Proteases for degradationProteases for degradation
classic protease:
highly site specific
not processive
chambered chambered protease:protease:processive and protective
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Many chambered proteasesMany chambered proteases
E. coli Rhodococcus Thermoplasma Saccharomyces
versions found in all organismsall function in protein degradation
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Eukaryotic 20 proteasomeEukaryotic 20 proteasome
alternative subunits for specialized P’somesalternative subunits for specialized P’somes
0.5 to 1% of the cellular protein0.5 to 1% of the cellular protein
can not degrade folded proteinscan not degrade folded proteins
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90o
x
Eukaryotic 20 proteasomeEukaryotic 20 proteasome
28 subunits, 14 separate proteinsactive sites inside; chamber can hold 100kD
how is specificity attained??
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Eukaryotic 26S proteasomeEukaryotic 26S proteasome
proteolysissubstrate recognitionsubstrate recognitionATP-dependent unfoldingATP-dependent unfolding
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Eukaryotic 26S proteasomeEukaryotic 26S proteasome
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QuickTime™ and aPNG decompressor
are needed to see this picture.
Specificity in protein degradationSpecificity in protein degradation
Ub
ubiquitin
76 a.a.8,000 mw
covalent additionof a small tag to markthe targetprotein fordestruction
only in eukaryotesvery highly conserved
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Specificity in protein degradationSpecificity in protein degradation
Ub
ubiquitin
76 a.a.8,000 mw
only in eukaryotesvery highly conserved
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CO2-Ub
NH3+
Protein
PROTEASOME
UbiquitinationUbiquitination
side chainlysine
UbUb
UbUb
UbUb
Protein
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.
.
Ub
Ub
Ub
Ub
Ub
Ub
Ub
Ub
Ub
Ub
20S core20S coreproteolysisproteolysis19S caps19S caps
binding, unfoldingbinding, unfoldingATP hydrolysisATP hydrolysis
Ubiquitin-proteasome degradationUbiquitin-proteasome degradation
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2004 Chemistry Nobel Prize2004 Chemistry Nobel Prize
AronAronCiechanoverCiechanover
AvramAvramHershkoHershko
IrwinIrwinRoseRose
www.nobelprize.orgwww.nobelprize.org
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Ubiquitin enzymologyUbiquitin enzymology
ATP
E1- Ub
Ub
E1
ubiquitinUb
E1 ubiquitin activating enzyme
E2E2- UbE2 ubiquitin conjugating enzyme (UBC)
S S-Ub
E3 E3 ubiquitin-protein ligase
S substrate
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R IN G -H 2
N
Hrd1p
CxxCx12-35CxHxxHxxCx8-39CxxC
RING-H2
HLSCLKNWMERSQT---CPIC
CTSCLTSWQESEGQG--CPFCHDHCIYRWLDTPTSKGLCPMC
c-CblApc11Hrd1
Ubiquitin ligase (E3) RING domainsUbiquitin ligase (E3) RING domains
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M B P
HIS6-huE1
Ub ATP
HIS6-huUBC4
H rd 1 p
R IN G
reaction mix
Δ Ub
each component isrequired
missing item
E1E2 E3 ATP
w.t. C399S
RING-H2dependent
UbGS
T-U
b
multi-Ubaddition
In vitro E3 activity of a RING domainIn vitro E3 activity of a RING domain
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The Cell Cycle and UbiquitinThe Cell Cycle and Ubiquitin
L. Hartwell, 2001 Nobel (with Nurse and Hunt)
QuickTime™ and aGIF decompressor
are needed to see this picture.
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The Cell Cycle and UbiquitinThe Cell Cycle and Ubiquitin
M-cyclin
S-cyclin
cyclin-dependentkinase
Ub-mediateddegradation
Ub-mediateddegradation
plus at least another layer
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The Cell Cycle and UbiquitinThe Cell Cycle and Ubiquitin
Cloning and analysis of CDC genes reveals two main classes of E3 involved in cell cycle control:
1) SCF complex
E3 subunits
2) APC - anaphase promoting complex
over 10 subunits, substrates include B cyclins, Pds1p
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F box adaptors for E3 specificityF box adaptors for E3 specificity
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F box adaptors for E3 specificityF box adaptors for E3 specificity
CUL1
SKP1
RBX1
F box adaptor
substrate
E2 Ub
RING domain
In many cases, the substrate-F boxinteraction is mediated by phosphorylation
BUT
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Oxygen sensing and ubiquitinationOxygen sensing and ubiquitination
CUL1
B/C
RBX1
VHL
HIF1
E2Ub
Cullin1/Rbx1Elongin B/CVHL tum. sup
High O2
Low O2
HIF1
HIF1
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Oxygen sensing and ubiquitinationOxygen sensing and ubiquitination
High O2 (HIF degraded)
HIF1 HIF1
OHbinding toCBCVHL E3
Low O2 (HIF stable)
HIF1
prolinehydroxylase
prolinehydroxylase
O2
oxygen-dependentmodification to an E3-binding sub.
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An SCF complex in detailAn SCF complex in detail
CUL1
SKP1
RBX1
SKP2
p27
E2 Ub
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Coordinates plus docking…Coordinates plus docking…
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SCF theme is broadly used in biologySCF theme is broadly used in biology
CUL
SKP1
RBX1
Adaptor
substrate
E2 Ub
Numerous cullins, numerous SKPs, over 50 E2sand a varitey of adaptors:
80 F box200 BTB domain proteins40 SOCS/BT (AYU Box)
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Ubiquitination and HIVUbiquitination and HIV
Vpu
CD4
Vpu
HIV-encoded Vpu programs proteasomal degradation of CD4
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CD4
VpuF WD40
CulSkp1Rbx
E2
Vpu
HIV-encoded Vpu programs proteasomal degradation of CD4 by recruiting the
cytoplasmic F-box protein TRCP
Ubiquitination and HIVUbiquitination and HIV
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p53 E6
E6AP
HECT domains: a distinct E3 familyHECT domains: a distinct E3 family
HPV 16, 18: cancer correlated, p53 degrading
HECT: HECT: HHomology to omology to EE6ap 6ap CC--TTerminuserminus
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Homology-driven discovery: p53 againHomology-driven discovery: p53 againMDM2: known regulator of p53 and
transcriptional target
p53MDM2
MDM2 has a functional RING domain
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MDM2-p53 regulationMDM2-p53 regulation
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MDM2-p53 inhibitorsMDM2-p53 inhibitorsIn Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 (2004) Vassilev et al. Science 303: 844
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MDM2-p53 inhibitorsMDM2-p53 inhibitorsIn Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 (2004) Vassilev et al. Science 303: 844
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Degradation and immunologyDegradation and immunology
plasma membrane
ER membrane
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DRiPs: the source of immune antigens?DRiPs: the source of immune antigens?
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DRiPs: the source of immune antigens?DRiPs: the source of immune antigens?
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Homology-driven discoveryHomology-driven discovery
Familial Parkinsonism: single gene defect
Model based on E3 function
Responsible gene: Parkin with RING-H2
pathologicalprotein(s)
production Parkinproduction
pathologicalprotein(s)
defectiveParkin
symptoms
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Destruction signalsDestruction signals
““degron”degron” distributeddistributedinformationinformation
direct recognitiondirect recognition
rec. of modification (F box)rec. of modification (F box)
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regulatoryevents
alteredstructure
Degradation in quality control and Degradation in quality control and protein regulation protein regulation
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Quality control in disease Quality control in disease
Alzheimer’sHuntington’sALS (Lou Gehrig’s)Parkinsonismcystic fibrosislong Q-T syndromeretinitis pigmentosaetc...
Alzheimer’sHuntington’sALS (Lou Gehrig’s)Parkinsonismcystic fibrosislong Q-T syndromeretinitis pigmentosaetc...
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Ubiquitin in Alzheimer’s plaques Ubiquitin in Alzheimer’s plaques
QuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.
amyloid ubiquitinatedproteins
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Quality control degradationQuality control degradation
-operates continuously in all cells
-important part of stress-responsepathways
-particularly important in non-dividing cells such as neurons
-significant therapeutic potential
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Quality control ligases of the ERQuality control ligases of the ER
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lysines: 6, 11, 27, 29, 33, 48, 63
UbUb
UbUb
UbUb
Alternative linkages for polyubiquitinAlternative linkages for polyubiquitin
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Multiple linkage sites in ubiquitinMultiple linkage sites in ubiquitin
Ub
multi-ubiquitin chains
C-48-C-48-C-48
C-29-C-29-C-29
C-63-C-63-C-63
48 linked
29 linked
63 linkedK63-linked chains are not targeted to proteasome
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63 linkage in TNF signaling63 linkage in TNF signaling
Ub
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63 linkage in TLR signaling63 linkage in TLR signaling
Immune signals
MyD88
IRAK
TRAF6
IKK
Ubc13/Uev1
fraction requiredfor TRAF6 action
TRAF6 catalyzes K63-linkedmulti-ubiquitin chain formation
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63 linkage in 63 linkage in TLR signalingTLR signaling
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Darwin’s phosphate…Darwin’s phosphate…
altered function
endocytosis of membrane proteins
ribosomal function- L29 protein (2000)
control of vacuolar traffic and delivery (2001)
regulation of DNA repair (2001)
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Fanconi’s anemiaFanconi’s anemia
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Fanconi’s anemiaFanconi’s anemia
Numerous human complementation groups
A, B, C, D1, D2, E, F, G
Cells senstive to IR and mitomycin C: DNA repair problems
D2 is mono-ubiquitinatedin responseto DNA damagingagents…
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Fanconi’s anemiaFanconi’s anemia
D2 is mono-ubiquitinatedin responseto DNA damagingagents…
D2 D2
A, C, E, F, G form a complex required for D2 mono Ub
B = D1 = BRCA2 !!
FANCL is the likely Ub ligase activity (!)
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Ubiquitin homologuesUbiquitin homologues
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Ubiquitin, SUMO Ubiquitin, SUMO and DNA repairand DNA repair