The 3D Structure Of Proteins Flashcards
What are the three ways in which the folding of a polypeptide chain is determined?
- the amino acid sequence
- the molecular structure and properties of the amino acids
- the molecular environment (ligands, cofactors, solvents and salts)
If the amino acid has a carboxylic group (COO-) what group is it in?
Charged or acidic
If the amino acid has an amine group (NH3+) what group is it in?
Charged or basic
If the amino acid has an amine (NH) or carbonyl (C=O) what group is it in?
Polar
If the amino acid has a hydroxyl (OH) what group is it in?
Polar
If the amino acid has a hydrocarbon what group is it in?
Non-polar hydrophobic
How does the polypeptide chain backbone form hydrogen bonds in the secondary structure?
The carboxyl and amine groups are polar
How are the variable side chains in the polypeptide chain usually arranged?
Trans formation
Why does the peptide bond in a polypeptide chain matter?
The delocalised electrons of the N-CO bond makes the bond ridged, with O and H atoms on opposite sides in the same plane
Around which bond is the rotational freedom found in the polypeptide?
The alpha carbon bond
Which amino acid has the most rotational ability and why?
Glycine, as its side group is only a hydrogen
What determines the conformation of the atoms in a polypeptide?
The minimisation of the energetic state
What happens if the delta G of a molecule is negative?
The molecule will spontaneously fold
What is the free energy of conformation affected by?
The environment:
- aqueous or lipid
- other proteins or molecules including salts and their ionic states
- charges in the environment that could induce further conformational changes
How do hydrophobic interactions work?
They’re driven by the minimisation of the chaos formed by being in an aqueous environment
How do covalent/ disulphide bonds form between neighbouring cysteines?
In an oxidative reaction. The SH groups from each cysteine cross link. This usually occurs in distant parts of the primary sequence but adjacent in the 3D structure. Can form intra-chain or inter-chain polypeptide chains
What are the two issues if proteins misfold?
- the function of a misfolded protein is lost or reduced
- misfolded proteins often have the tendency to self-associate and aggregate
What is the protein that misfolded in Huntington’s?
Huntingtin Htt
What is the protein that misfolded in Alzheimer’s?
Amyloid-beta
What is the protein that misfolded in creutzfeldt-Jacob’s disease?
Prion protein
What is the protein that misfolded in Parkinson’s?
Alpha-synuclein
What is the protein that misfolded in AAamyloidosis?
Serum amyloid A
What is the protein that misfolded in type 2 diabetes?
Islet amyloid peptide
What happens in cystic fibrosis?
Misfolded proteins result in cellular processing that leads to their degradation
How does somatic mutations in the gene sequence lead to the protein misfolding?
They lead to a protein that is unable to adopt the native folding
How does errors in transcription/translation lead to the protein misfolding?
Lead to a modified protein which is unable to fold properly
Give some reasons for proteins misfolding
- Failure of the folding machinery
- mistakes of the post-translational modifications or in trafficking of proteins
- structural modifications produced by environmental changes
- induction protein misfolding by seeding and cross seeding by other proteins
What is observed in Alzheimer’s (on a biological level)?
Proteolytic cleavage or amyloid precursor protein (APP) is observed
What is the main function of APP and what does cleaving of it result in?
Involved in G-protein signalling
Cleaving results in a 40 residue peptide (beta amyloid) it accumulated and misfolds to form beta sheets
What does misfolding of APP mean?
A planar arrangement and polymerisation takes place, which forms fibrils (amyloid fibrils), then fibres and staked beta sheets in which the side chains interdigitate
What is the most common mutation in cystic fibrosis?
A deletion of phenylalanine at residue 508 of the cystic fibrosis transmembrane conductance regulator (CFTR)
What does the mutation mean in cystic fibrosis?
- A misfolding of the protein whilst it is still in the ER
- recognised by the cellular machinery which results in ubiquitination, trafficking to the proteasome and degradation
What are prions?
Misfolded proteins that interact with other normal proteins
What do prions do?
Induce misfolding of the normal protein and polymerisation
What does an oligomer do?
Forms fibrils of misfolded protein
What is the oligomer process reliant on?
The concept of energy minimisation and is a dynamic process brought about by the interaction of molecules resulting in a more stable, aggregated structure
