Lecture 14 Protein-AA Synthesis and Breakdown Flashcards
Describe protein synthesis
- cell signalling
- transcription
- translation and elongation
- folding of linear polypeptide
Regulation of protein synthesis
Ability to express biologically active or funtional proteins regulated by:
1. DNA transcription
2. RNA processing
3. mRNA stability
4. mRNA translation
5. post-translational protein modifications and folding
What is critical to the function of proteins?
Their structure
What happens with alterations in protein structure?
Results in numerous diseases arising from
1. abnormal genes (mutations, polypmorphisms, deletions)
2. abnormal processing of proteins during synthesis
3. inability to degrade abnormal proteins
Common diseases of SNP mutations
- sickle cell anemia
- familial hypercholesterolemia
- connective tissue disorders
- neonatal diabetes-insulin mutation
Describe sickle cell anemia
single nucleotide polymorphism (SNP) mutation where a single hydrophobic AA is substituted for an acidic AA in the β-chain of Hb which alters the structure of Hb, and it cannot maintain oxygen properly. The deoxygenated proteins polymerize and precipitate within the erythrocyte causing a sickle shape that is rigid and sticky (cant carry O2) and can cause ischemia
Describe Familial Hypercholesterolemia
Defects in gene encoding the low density lipoprotein (LDL) receptor resulting in synthesis of abnormal LDL receptors which cannot bind LDLs properly thus cells cannot take up cholesterol causing an increase in serum cholesterol and leads to early atherosclerosis
Describe Connective Tissue disorders
collagen is the most abundant protein in the body and abnormal genes that alter collagen structure result in many diseases
* i.e. Single-base substitutions convert a codon for glycine to a codon for another AA (bulkier side chain) which interferes with folding of triple helix or self-assembly of collagen into fibrils
* other mutations include deletions, insertions, RNA splicing mutations
Describe Neonatal Diabetes-insulin mutation
10 mutations identified, these mutations alter the way insulin folds during its synthesis
* Improperly folded proteins interfere with other cellular processes in ways that eventually kill the cells that produce insulin
What is the importance of proper protein degradation?
-
regulates protein abundance: cell growth, proliferation, differentiation, immune, inflammatory response, apoptosis and metabolic adaptation
* elimination abnormal proteins: mis-folded, miscoded, mis-localized, damaged proteins
What are the major pathways of protein degradation?
- UPS: Ubiquitin -proteosome system
- ERAD: ER-associated degradation
- ALP: Autophagy-lysosomal pathway
- Calcium/ calpain-dependant system
What is the most common pathway for protein degradation?
the UPSystem
* 80-90% of protein degradation
* ubiquitin: universal garbage tag
What is the UPSystem responsible for degrading?
degradation of abnormal, damaged, denatured, or mislocated proteins & regulatory proteins (short half-lives, i.e. <30 mins)
When does the UPSystem appear to increase activity?
during pathological conditions (sepsis, cancer, trauma) & starvation
* Cytokines may be involved (in part) with activation
Describe the UPS system
- poly-ubiquitination: proteins to be degraded are ligated to ubiquitin (tagged) in an ATP-requiring reaction with a bunch of processes
- Proteolysis in 26S proteasome: The proteasome is a large, oligomeric structure with a cavity where protein degradation occurs, essentially a garbage compactor
Describe the ALPathway
Autophagy-lysosomal pathway is a way to get rid of large cargo by putting a membrane around the cargo and then a lysosome will fuse with the membrane and release digestive enzymes to break down the cargo.
* big cargo like mito
