Protein degradation Flashcards
Define quality control.
The cellular mechanisms that recognize and remove the hydrophobic patches on proteins.
What are the two aims of proteolysis?
- quality control: to remove unwanted proteins by protein re-folding and proteolysis
- to regulate various cellular processes
Where does non-selective proteolysis take place?
lysosome
Where are extracellular proteins degraded?
lysosome
where are intracellular proteins degraded?
proteosome
where does selective proteolysis take place?
proteosome
List several lysosomal storage diseases.
- hurler’s disease
- tay-sach’s disease
- gaucher disease
- fabry disease
**all defects in breakdown of certain materials
What are the steps from misfolding of a protein to cell damage/disease?
misfolding -> aggregation -> precipitation -> cell damage/disease
List the neurodegnerative diseases caused by protein aggregation.
- alzheimer’s
- parkinson’s
- huntingtons
- ALS
Describe the ER unfolded protein response.
- after protein synthesis on rough ER, ER proteins are directly translocated into the lumen and ER chaperones help protein folding into final conformation
- correctly folded proteins are packaged into vesicles and targeted to their final destinations
- incorrectly folded or misfolded proteins are targeted to the proteosome for degradation
Define selective proteolysis.
Degradation in proteosome by ubiquitinated proteins
Describe the beta subunits that give the proteolytic chamber its activity.
- chymotrypsin-like (preference for tyrosine or phenylalanine)
- trypsin-like (preference for arginine or lysine)
- post-glutamyl (preference for glutamate or other acidic residue)
what does the proteosome antechamber do?
It is a place for unfolded proteins to be stored before they enter the central chamber
What are the subunits of the proteosome chamber ring?
a1-a7/b1-b7/b1-b7/al-a7
Describe ubiquitin
76 amino acid peptide with seven internal lysines (for polyubiquitnation)
How is ubiquitin linked to the protein?
carboxy-terminal glycine of ubiqutin is linked to lysine of the protein of interest. Other ubiqutiins are then added to internal lysines of the first ubiqutiin
Roles of ubiqutiin.
- histone regulation (mono-ub)
- endocytosis (multi-ub)
- proteosomal degradation (poly-ub at lys 48)
- DNA repair (poly-ub)
Where is ATPase used in ubiquitination?
activation of ubiquitin by ubiquitin activating enzyme, E1 (C-term glycine linked to cysteine of E1)
Ubiquitin conjugating enzyme
E2
Ubiquitin ligase
E3
To what protein does the ub degradation signal of a protein bind?
E3
Poly-ub chain conjugating factor
E4
Which enzyme does poly-ub proofreading and targetng to 26S proteosome?
E4
Optimal ubiquitin chain length
4-6
What type of structure is formed from prion disease?
cross-beta filament aggregate
Conformational change of prion protein when it is infectious
two alpha helices to four beta sheets
How can E3 ligases be activated?
modifications: phosphates, ligands, allosteric binding
How are degradation signals activated
phosphorylation, unmasking, destabilizing N-terminus
Consequences of ubiquitination
- changing conformation to modulate protein activity
- creating protein binding sites (i.e. to E3 ligase)
- masking protein binding sites
Ubiquitin domain protein
domains related to ubiqutiin in sequence but are otherwise unrelated. these domains are responsible for recruitment of ubiquitinated substrates to the proteosome
Ubiquitin like modifier
functions in analagous manner to ubiqutiin
have similar structure to ubiqutiin
all have C-term glycine and go through same conjugation process
some types of ubiquitin like modifier
sumoylation
nedylation
Atg
Urm
how are ubiquitin like modifiers processed
many UBLs are synthesized as precursors and need to be processed by UBL-specific isopeptidases to expose C-terminal glycine that is activated and linked to E1
How are sumoylation and ub different
cause different consequences to protein functions
- ub of PCNA clamp causes error-free DNA repair
- sumoylation of PCNA clamp causes DNA replication and inhibits repair
Function of 19S proteosome cap
six subunit protein ring and ATPases to unfold protein after binding to Ub signal and cleaving it. proteins AAA called unfoldases
True or false. the proteosome is very large
true. 26S
