The 3D Structure Of Proteins

Question 1

What are the three ways in which the folding of a polypeptide chain is determined?

Answer 1

• the amino acid sequence
• the molecular structure and properties of the amino acids
• the molecular environment (ligands, cofactors, solvents and salts)

Question 2

If the amino acid has a carboxylic group (COO-) what group is it in?

Answer 2

Charged or acidic

Question 3

If the amino acid has an amine group (NH3+) what group is it in?

Answer 3

Charged or basic

Question 4

If the amino acid has an amine (NH) or carbonyl (C=O) what group is it in?

Answer 4

Polar

Question 5

If the amino acid has a hydroxyl (OH) what group is it in?

Answer 5

Polar

Question 6

If the amino acid has a hydrocarbon what group is it in?

Answer 6

Non-polar hydrophobic

Question 7

How does the polypeptide chain backbone form hydrogen bonds in the secondary structure?

Answer 7

The carboxyl and amine groups are polar

Question 8

How are the variable side chains in the polypeptide chain usually arranged?

Answer 8

Trans formation

Question 9

Why does the peptide bond in a polypeptide chain matter?

Answer 9

The delocalised electrons of the N-CO bond makes the bond ridged, with O and H atoms on opposite sides in the same plane

Question 10

Around which bond is the rotational freedom found in the polypeptide?

Answer 10

The alpha carbon bond

Question 11

Which amino acid has the most rotational ability and why?

Answer 11

Glycine, as its side group is only a hydrogen

Question 12

What determines the conformation of the atoms in a polypeptide?

Answer 12

The minimisation of the energetic state

Question 13

What happens if the delta G of a molecule is negative?

Answer 13

The molecule will spontaneously fold

Question 14

What is the free energy of conformation affected by?

Answer 14

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

Question 15

How do hydrophobic interactions work?

Answer 15

They’re driven by the minimisation of the chaos formed by being in an aqueous environment

Question 16

How do covalent/ disulphide bonds form between neighbouring cysteines?

Answer 16

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

Question 17

What are the two issues if proteins misfold?

Answer 17

• the function of a misfolded protein is lost or reduced

- misfolded proteins often have the tendency to self-associate and aggregate

Question 18

What is the protein that misfolded in Huntington’s?

Answer 18

Huntingtin Htt

Question 19

What is the protein that misfolded in Alzheimer’s?

Answer 19

Amyloid-beta

Question 20

What is the protein that misfolded in creutzfeldt-Jacob’s disease?

Answer 20

Prion protein

Question 21

What is the protein that misfolded in Parkinson’s?

Answer 21

Alpha-synuclein

Question 22

What is the protein that misfolded in AAamyloidosis?

Answer 22

Serum amyloid A

Question 23

What is the protein that misfolded in type 2 diabetes?

Answer 23

Islet amyloid peptide

Question 24

What happens in cystic fibrosis?

Answer 24

Misfolded proteins result in cellular processing that leads to their degradation

Question 25

How does somatic mutations in the gene sequence lead to the protein misfolding?

Answer 25

They lead to a protein that is unable to adopt the native folding

Question 26

How does errors in transcription/translation lead to the protein misfolding?

Answer 26

Lead to a modified protein which is unable to fold properly

Question 27

Give some reasons for proteins misfolding

Answer 27

• 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

Question 28

What is observed in Alzheimer’s (on a biological level)?

Answer 28

Proteolytic cleavage or amyloid precursor protein (APP) is observed

Question 29

What is the main function of APP and what does cleaving of it result in?

Answer 29

Involved in G-protein signalling

Cleaving results in a 40 residue peptide (beta amyloid) it accumulated and misfolds to form beta sheets

Question 30

What does misfolding of APP mean?

Answer 30

A planar arrangement and polymerisation takes place, which forms fibrils (amyloid fibrils), then fibres and staked beta sheets in which the side chains interdigitate

Question 31

What is the most common mutation in cystic fibrosis?

Answer 31

A deletion of phenylalanine at residue 508 of the cystic fibrosis transmembrane conductance regulator (CFTR)

Question 32

What does the mutation mean in cystic fibrosis?

Answer 32

• 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

Question 33

What are prions?

Answer 33

Misfolded proteins that interact with other normal proteins

Question 34

What do prions do?

Answer 34

Induce misfolding of the normal protein and polymerisation

Question 35

What does an oligomer do?

Answer 35

Forms fibrils of misfolded protein

Question 36

What is the oligomer process reliant on?

Answer 36

The concept of energy minimisation and is a dynamic process brought about by the interaction of molecules resulting in a more stable, aggregated structure