Ubiquitylation Flashcards
How many genes are there in the human genome?
How many transcripts?
How many proteins?
20,000 genes
100,000 transcripts
Over 1,000,000 proteins
How many transcripts are produced from these genes?
100,000 transcripts
How many proteins are generated from these transcripts?
Over 1,000,000 proteins
What increases protein complexity and dynamics?
Post translation modifications
What may affect specificity and accuracy of protein function?
Post translational modifications (PTM)
What is an example of protein activity modification?
Phosphorylated c-Jun is more active than c-Jun
What modifications affect DNA recognition?
Acetylation and methylation of chromatin
What is an example of protein folding modification?
Cyclin-CDKs interaction in cell cycle
What is an example of protein translocation?
Translocation of NF-kB from cytoplasm to nucleus
What does the UPS mediated protein ubiquitination affect?
Stability and degradation of proteins, e.g., beta catenin level in WNT signalling
What is the Ubiquitin Proteasome System (UPS)?
A system that targets specified proteins for degradation
What is ubiquitin?
A small, highly conserved globular protein resistant to heat, pH, and proteolysis
How many amino acids does ubiquitin have?
76 amino acids
Where is ubiquitin found?
In eukaryotes and archaea, not found in eubacteria
What are the three different fusion proteins of ubiquitin?
UBA, UBB, UBC
What is the RGG motif?
A conserved motif at the C terminal tail that can link to lysine residues on substrates
What are K48 linked chains associated with?
Targeting substrate for degradation via 26S proteasome
What are K63 linked chains involved in?
DNA repair and various forms of receptor signalling
What are the three types of enzymes mediating ubiquitylation?
E1 (activating enzymes), E2 (conjugating enzymes), E3 (ligases)
What is the function of E1 enzymes?
Ubiquitin activating enzymes that require ATP
What is the function of E2 enzymes?
Ubiquitin conjugating enzymes that share an active site Ub-binding cysteine residue
What are HECT E3s?
Homologous to E6AP C-Terminus, with ~20 members
What are RING E3s?
Really Interesting New Gene, with >700 members
What is the SCF complex?
A type of Cullin ring ligase with a substrate specific part: F-box
What is the function of the 26S proteasome?
Degradation via the proteasome enzyme
What are deubiquitinating enzymes (DUBs)?
> 100 enzymes that cleave Ub-fusions and ubiquitin from proteins
What is USP28 associated with?
Overexpression in cancers including colon and lung
What is a PEST sequence?
Rich in proline, glutamic acid, serine, threonine
What is the D (destruction) box?
RXXL sequence found in mitotic cyclins
What does the N-end rule target?
Proteins with an acetylated N-terminal residue
What is HPV associated with?
> 99% of cervical cancer cases
What are the oncogenic genes expressed by HPV?
E6 and E7
What does E6 target?
p53 by subverting the action of normal cellular E3 enzyme
What does E7 bind to?
pRB leading to its ubiquitylation and degradation
What is FBXW7 associated with?
Colorectal cancer and substrates like C-Myc, c-jun, Notch, Cyclin B
What happens when Fbxw7 cannot associate with FAPs?
They are not marked for degradation, associated with hallmarks of cancer
What is the role of B-catenin?
Key protein in cadherin junction and Wnt pathway
What happens in the absence of Wnt?
B-catenin forms a destruction complex leading to its degradation
What occurs when Wnt binds to its receptor?
B-catenin is released and translocates into the nucleus
What is C-Cbl?
A proto-oncogene encoding RING finger E3 ubiquitin ligase
What is MDM2 responsible for?
Ubiquitylation of p53
What is multiple myeloma?
An incurable cancer causing accumulation of cells in bone marrow
What is a treatment for multiple myeloma?
Proteasome inhibitor: Bortezomib / Velcade
