Protein Folding Flashcards
(12 cards)
Why is a defined 3D shape necessary?
- biological function requires them to adopt a defined 3D shape
- catalysis requires a high degree of atomic alignment
- dictates shape of protein
- has to fold very very precisely in order to allow prosthetic group to bind
- molecular recognition
- can cause misfolding if not done accurately
What can mutations cause?
- misfolding and disease
- loss of function
- formation of toxic aggregates = cell death
- abnormal cell morphology
- abnormal collagen assembly, deficient connective tissue = diseased state
What can protein misfolding cause?
- mislocalisation = protein not transported to its final destination
- accumulation in the ER
- degradation
- loss of functional enzymes, receptors and tumour suppressors
- extracellular toxic aggregates (amyloid plaques)
- intracellular deposits
- neurodegeneration
- abnormal collagen assembly or extracellular matrix proteins
- connective tissue diseases
- abnormal cell or tissue morphology = impaired functions
What are intrinsically disordered proteins (IDPs)
- Proteins that are not completely folded = contain regions that are intrinsically unstructured in their normal state
- Compositional bias = low complexity & low proportion of Val, Leu, Ile, Met, Phe, Trp, Tyr = lack of hydrophobic residues
- Disordered regions may fold upon binding to their biological target
- May have flexible linkers which facilitate formation of assemblies & binding to targets
Hypothetical protein folding pathways
Folding starts with formation and then association of some key secondary structure elements = intermediates
Principles of thermodynamics
∆G = ∆H-T∆S
Reaction is energetically favourable (occurs spontaneously) when ∆G is negative
What happens when there is a decrease in enthalpy?
Exothermic interactions
Folding of the polypeptide chain brings groups together and generates multiple opportunities for favourable interactions
Thermodynamics of protein folding
- folding of the polypeptide chain restricts severely its degrees of freedom (from many unfolded conformations to one folded conformation)
- this is unfavourable from the view of entropy as order has increased
- favourable increase in entropy comes from displacement of water around the unfolded chain
- water molecules overall increase their randomness = residues don’t interact with water so disorder increases
Hydrophobic effect
- hydrophobic amino acid side chains associated with each other, causing a polypeptide chain to collapse into a hydrophobic core
- the driving force for protein folding is the large increase in entropy from the release of water previously around the hydrophobic groups
- hydrophobic side chains are in the interior
- polar and charged side chains (hydrophilic) remain on the surface facing water
- hydrophobic collapse of a polypeptide occurs at the same time as formation of secondary structure
Role of chaperone proteins
Stabilise intermediates, minimise misfolding and prevent aggregation
Folding in the cytosol
- Chaperones optimise the yield of correctly folded proteins
- Some allow coordination of the assembly of multi-subunit proteins (formation of quaternary structure)
This requires energy
Heat shock proteins
- produced by cells in response to stressful conditions
- named by molecular weight —> Hsp60 is 60 kDa, Hsp70 is 70 kDa etc
- the best characterised is the Hsp60/Hsp10 complex
