Week 4 Flashcards
With what essential amino acid is transcription always started?
Methionine
What are the 2 pathways for protein degradation?
Lysosomal - long half-life, membrane proteins, extracellular proteins
Proteosomal - short half-life, key metabolic enzymes, defective proteins
What are the stages of protein folding?
Primary (aa sequence) → secondary (local folding - α helices and β pleated sheets) → tertiary (long-range folding) → quarternary (multimeric organisation) → supramolecular (large scale assemblies) → function
What is proteostasis?
Protein homeostasis
Synthesis, folding, processing, assembly, trafficking, localisation, degradation
What are the components of an amino acid?
Amino group Carbon chain Hydrogen R-group Carboxyl group
How are α helices formed?
H bond forms between carbonyl oxygen atom of each peptide bond and amide H atom from an amino acid 4 positions towards the C-terminus
What are the main features of α helices?
Periodic spiral
Directionality
R groups face outwards
How many amino acids are in a single turn of an α helix?
3.6
How are β pleated sheets formed?
Each strand is 5-8 aa residues
Hydrogen bonding between strands of polypeptide form the planar sheet
What are the main features β pleated sheets?
Directionality is parallel anti-parallel
R groups project from both faces of the sheet
What types of bonding are present in tertiary protein structures?
Hydrophobic bonds (non-polar R groups) Hydrogen bonds (polar R groups) Disulfide bonds
What is protein conformation determined by?
Primary structure
Why is there a tendency for proteins to aggregate?
Cellular environment is crowded (300-400 g/l)
What is a molecular chaperone?
Any protein that interacts with, stabilises or helps another protein to acquire its functionally active conformation, without being present in its final structure
Selectively bind to short stretches of hydrophobic amino acids
E.g. chaperonin
What percentage of newly synthesised proteins are misfolded?
30%
What enzyme is responsible for deciding if a protein is misfolded and how does it do this?
Glucosyltransferase
Detection of stretches of hydrophobicity on the outside (will encourage aggregation which is detrimental)
Outline the process of quality control in the ER
Newly synthesised protein → glycosylated in ER (chain of specialised sugar groups on the end) → glucosidase I and II will cleave all sugar groups except 1 → binds to chaperone (e.g. calnexin/calreticulin) which aids folding → glucosidase II cleaves the final sugar group → correctly folded proteins leave; incorrectly folded proteins will be refolded )
What happens when the same protein is misfolded several times?
Sent to proteasome for degradation
What is the structure of a proteasome?
Hollow, cylindrical structures
CAP
α-subunits (non-enzymatic, structural)
β-subunits (proteolytic activity, destroy protein)
Outline the process by which proteins are labelled for destruction and destroyed
Polyubiquitination (labelling) → label recognised by CAP of proteasome → label removed and protein unfolded → protein threaded through proteasome and proteolysis occurs
What are proteinopathies?
Protein folding diseases
Accumulation of misfolded proteins resulting in aggregates, thereby gaining toxic activity or losing the normal function
What types of protein are aggregated in amyloidosis?
Aβ - Alzheimer’s
ABri - familial British dementia
ADan - familial Danish dementia
PrP - Creutzfeldt-Jakob disease (prionopathy)
What types of protein are aggregated in tauopathy?
Hyperphosphorylated Tau - Alzheimer’s, fronto-temporal lobar degeneration etc.
What types of protein are aggregated in synucleopathy?
α-synuclein - Parkinson’s, Lewy Body dementia
