Sjogren: Lecture 5 Protein degradation and implications for therapeutics Flashcards
What is the role of chaperones in folding and function of proteins?
Chaperones help the covalent folding/unfolding of proteins properly.
Disorders associated with mutations in chaperones can affect muscle, bone and the central nervous system.
Examples of chaperone proteins are heat shock proteins (HSP60, HSP70 and HSP90)
What is the role of of posttranslational modifications (PTMs) ?
They add complexity and variability to the proteome.
Different mechanism can lead to different functions. Examples include activation, degradation, regulation and modulation.
What is important to know about protein degradation?
It is essential to remove misfolded and dysfunctional proteins.
Plays an essential role in proteostasis
Break down dietary proteins to supplement amino acid synthesis.
Regulation of cellular processes (transcription and signal transduction.
How does degradation occur?
It happens by different processes in order to handle turnover of normal cellular proteins. Including the role of regulating protein levels.
What are the different protein degradation processes you need to know?
There are 5 total but we only need to know 3.
Ubiquitin-proteasome proteolysis - proteins are targeted for degradation
Lysosomal digestion - these are membrane bound organelles that have proteases. They can degrade exogenous proteins/ damaged organelles.
Autophagy - Turned up during stress and maintains normal cellular function by getting rid of damaged organelles.
What disease states are attributed to improper protein degradation and then accumulation of aggregated proteins?
Alzheimer’s disease and Huntington’s disease.
How does the ubiquitin-proteasome system work?
They both work together to degrade proteins in a targeted fashion.
E1, E2 and E3 attaches ubiquitin chains to lysine residues on target proteins
E3 ligases confer specificity and recognize degrons on their substrates.
What are therapeutic treatments/target proteins associated with protein degradation?
Bortezomib (Velcade) is the 1st approved proteasome inhibitor.
Ongoing clinical trials for E3 ligase-substrate inhibition and PROTACs.
