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IMS > Proteins- Protein structure, relating structure to function – haemoglobinopathies and proteins in health and disease > Flashcards

Proteins- Protein structure, relating structure to function – haemoglobinopathies and proteins in health and disease Flashcards

1
Q

Genome

A

Full set of genes in an organism

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2
Q

Proteome

A

Full set of proteins encoded by the human genome

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3
Q

Amino acid structure

A
  • Central C atom
  • Amino group
  • Carboxyl group
  • Variable group
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4
Q

Categorising R groups

A
  • Size (large/small)
  • Shape (aliphatic/aromatic)
  • Hydrophobicity (polar/ non-polar)
  • Charge (acidic/basic)
  • Sulfur-containing (cysteine and methionine)
  • Imino (proline is not an amino acid)
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5
Q

Chiral

A

4 different groups attached to a central C atom

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6
Q

Amino acids with non-polar side chains

A

VITALGMPP- Valine, isoleucine, tryptophan, alanine, leucine, glycine, methionine, phenylalanine, proline

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7
Q

Amino acids with polar side chains

A

GCATTS- Glutamine, cysteine, asparagine, tyrosine, threonine, serine

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8
Q

Electrically charged side chains

A

Basic- HAL- Lycine, arginine, histidine

Acidic- AG- Aspartate, glutamate

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9
Q

pKa

A

The pH at which the group is 50% dissociated/ ionised

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10
Q

pI

A

pH at which the molecule has no overall charge

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11
Q

Charge on a histidine molecule

A

At pH 7 the histidine sidechain will be mainly uncharged

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12
Q

Which amino acid is not chiral?

A

Glycine as has a R group of H

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13
Q

If pH is below pKa will group have H attached?

A

Yes

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14
Q

If pH is above pKa will group have H attached?

A

No

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15
Q

Structure of a protein

A

Primary structure- amino acid sequence
Secondary structure- local arrangements of amino acids in the peptide chain
Tertiary structure- organisation of the primary and secondary structures into the 3D protein shape
Quaternary structure- more than one polypeptide chain. The arrangement of folded chains that make up a protein

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16
Q

What are amino acids joined by?

A

Peptide bonds

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17
Q

What is called the backbone of an amino acid?

A

Amino acid chain

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18
Q

What is called a polypeptide chain in an amino acid?

A

Residue

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19
Q

What are different R groups called in an amino acid?

A

Side chains

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20
Q

Peptide bonds have partial double bond characteristics as it resonates between two forms- what are they?

A

The carbon-nitrogen bond shows some double bond characteristics and some limited rotation around the bond. The O and H atoms are on opposite sides of the bond, this is the trans position which maintains the maximum distance between them which is sterically most advantageous.

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21
Q

Two types of secondary structure

A

Alpha helix- formed by backbone of the chain and the side chain extend out of the helix, interchain and intrachain HB.

Beta pleated sheets- polypeptide chains run alongside of each other. May be several strands making up a beta chain that are part of the same chain so HB between them are intrachain bonds. There is interchain bonds between different amino acid chains. The side chains lie above or below the plain of the sheet

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22
Q

Difference between inter and intrachain bonds

A
  • Intrachain HB- these are bonds that occur between different parts of the same chain- in alpha helixes
  • Interchain HB- HB between different chains
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23
Q

Beta pleated sheets backbone

A
  • No elasticity
  • Pleated/zigzag shape due to the tetrahedral bonding
  • R-groups lie outside the plane of the sheet
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24
Q

Protein structure- tertiary and quaternary

A

Tertiary structure are proteins that have a compact 3D structure but are flexible. Tertiary structure is the overall 3D shape of a protein. It involves the close packaging of the secondary structure.

Quaternary structure- some proteins have more than one polypeptide chain.

The individual polypeptide chains are called sub-units.

Quaternary structure is the arrangement in space of the sub-units.

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25
Q

Forces that stabilise tertiary and quaternary structures

A

Disulphide bonds found between two cysteine (contains S). When two Cys residues are brought together they can form a disulphide bond. E.g. antibodies and insulin

Electrostatic interactions- stabilise the tertiary and quaternary interactions between oppositely charge side chains. These interactions are called salt bridges and are called an ion pair.

Van der Waals- reactions occur between neutral molecules and rely on dipoles. Stronger the dipole, the stronger the reaction. Dipoles can be permanent or induced. Dipoles occur across covalent bonds with atoms of different electronegativity. Electron density around atoms can be uneven.

HB- H can bond to F/O/N- most polar residues can HB - all but amino acids with non-polar side chains

Hydrophobic effect- most important effect in stabilising proteins

Non-polar amino acids try to minimise contacts with water and are buried in the core of proteins in aq solution. Energetically favourable for non-polar molecules interfere with the water molecules so doesn’t prevent any HB. Polar amino acids are found on the surface of protein or are HB in the core

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26
Q

Proteins folding is prevented by?

A
  • The rigidity of the peptide bond limits the flexibility of the chain
  • The physical and chemical properties of the side chains
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27
Q

What proteins that assist protein folding?

A

Chaperones assist protein folding. The amino acid sequence contains all the information needed to ensure correct protein folding.

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28
Q

Chaperonins definition

A

Form folding chambers which provides a stable environment to encourage correct folding

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29
Q

Protein misfolding diseases- Alzheimer’s disease

A

Symptoms- mental deterioration, lack of ability to speak, confusion, mood swings and death
Biochemical basis:
• A fragment from a normal membrane protein, amyloid precursor protein, accumulates and aggregates forming insoluble fibrils of amyloid beta protein in the brain.
• The fibrils aggregate to form plaques. These plaques damage and destroy neurones.

30
Q

Protein misfolding diseases- Cruetzfeldt Jacob disease

A
  • Loss of neurological function, memory loss, loss of coordination ad language ability, coma and death. Some hereditary form exist but is also associated with the ingestion of an infectious agent, the prion protein PrPSc (not a virus). Similar to Kuru (a disease from cannibalistic humans).
    Biochemical basis- PrPSc has an identical primary sequence to a normal membrane protein PrPc but has a higher proportion of Beta pleated sheet. Contact of normal soluble PrPc protein (mostly alpha-helical) with abnormal form PrPSc (mostly Beta pleated sheet) causes the PrPc protein to acquire the abnormal PrPSc structure.
31
Q

Types of protein

A

Globular proteins e.g. enzymes, haemoglobin

•compact, soluble – hydrophilic residues outside, hydrophobic residues hidden

Fibrous proteins e.g. keratin (hair/nails), collagen

•elongated, often have repeating amino acid sequences, insoluble due to high hydrophobic amino acid content

32
Q

Uses of Hb

A
  • cells require oxygen for oxidation of food
  • O2 only sparingly soluble in blood, therefore need transport and storage system- doesn’t provide a sufficient amount of oxygen for metabolic needs
33
Q

Difference between Hb and Mb

A

Myoglobin (Mb): Oxygen store

Haemoglobin: Oxygen transport (CO2 transport)

34
Q

Myoglobin (Mb) appearance and function

A
  • Stores oxygen in tissues
  • Highest concentration in skeletal and cardiac muscle
  • Small protein
  • Very compact
  • Contains haem prosthetic group
  • Mostly alpha helical (8 alpha helices)
  • Hydrophobic residues on inside, polar ones on surface
35
Q

Haem prosthetic group

A

Tightly bound, non-polypeptide unit essential for biological activity of protein.

Non-covalently bound in a hydrophobic crevice in protein.

Oxygen binding changes position of Fe. The iron ion sits outside the plain of the ring when not bound to oxygen. When oxygen binds to the iron ion it alters the position of the iron ion and pulls it into the plain of the ring.

36
Q

Advantages of associating haem unit with protein molecule

A
  1. Fe atoms are kept in Fe2+ form- Fe3+ doesn’t bind to oxygen
  2. Binding of other small molecules e.g. carbon monoxide is inhibited
37
Q

Haemoglobin (Hb) structure

A
  • Four polypeptide chains held together by non-covalent interactions
  • Adult haemoglobin have 2, 2β chains
  • Each chain contains a haem group, therefore Hb can bind four O2
  • Four chains packed tightly together in a tetrahedral array with overall spherical shape.
  • Quaternary structure

Hb is an allosteric protein (changes shape when something binds to it) - the binding of O2 to one subunit affects interactions with the other subunits.

38
Q

Difference between Hb and Mb

A

Oxygen binding- Hb-Co-operative Mb-Non co-operative
Oxygen affinity- Hb-pH and carbon dioxide dependent Mb- Not pH or carbon dioxide dependent
Regulation Hb-Regulated by BPG Mb-Not regulated by BPG

39
Q

Does Mb or Hb have a higher affinity for oxygen?

A

Mb has a greater affinity for oxygen than Hb.

40
Q

What happens when oxygen binds to Hb?

A

Alters the position of the iron ion in the same way as Mb. Once oxygen binds the helices get closer.

Proximal His and Distal His move closer to the porphyrin ring.

Effects of oxygen binding to one Hb subunit:

  • proximal His is pulled in towards the porphyrin ring
  • shifts helix F, EF and FG corners
  • altered shape transmitted to subunit surfaces
  • some interchain salt bridges rupture
  • As the subunit changes shape, it therefore changes the relationship between the 4 subunits
  • The alphabeta pairs slide and rotate relative to one another
41
Q

Change in relative position of Hb subunits affects O2 binding

A

T state – ‘tense state’ – more salt bridges between subunits- O2 binding sites not accessible
Low affinity for O2

R-state – ‘relaxed state’ – fewer salt bridges- O2 binding sites more accessible
High affinity for O2

42
Q

Bohr effect- change in pH

A

Less oxygen so need to release into cells so affinity decreases.

The decrease in the oxygen affinity of Hb in response to decreased blood pH resulting from increased carbon dioxide concentration in the blood.

Increase in [H+] (lowering of pH) decreases affinity of Hb for O2.
Increased CO2 in blood or increased lactic acid will lower pH.
Increased release of O2 to respiring rapidly tissues or muscle releasing lactic acid.

High concentrations of CO2 promote dissociation of O2 from Hb. This occurs through the production of carbonic acid which dissociates to yield a proton and decreases pH.

The decrease in the oxygen affinity of Hb in response to decreased blood pH resulting from increased carbon dioxide concentration in the blood.

Increase in [H+] (lowering of pH) decreases affinity of Hb for O2.
Increased CO2 in blood or increased lactic acid will lower pH.
Increased release of O2 to respiring rapidly tissues or muscle releasing lactic acid.

High concentrations of CO2 promote dissociation of O2 from Hb. This occurs through the production of carbonic acid which dissociates to yield a proton and decreases pH.

43
Q

Why do H+ ions affect oxygen binding?

A

pH affects the protonation state of amino acid residues- particularly histidine residues.

When [H+] is high, additional residues are protonated – particularly histidine residues.

Additional positively charged residues can form new salt bridges – these stabilise the T-state and decrease affinity for O2 – release oxygen.

Salt bridges form between positive and negative residues.

44
Q

Regulation by biphosphoglycerate (BPG)

A
  • BPG found at high concentration in erythrocytes ( a RBC)
  • BPG levels increase at high altitude and in hypoxia (poor oxygenation of peripheral tissues)
  • BPG decreases affinity of Hb for O2 so causing more oxygen release in these conditions

BPG binds in the space between the β subunits – in the T-state only- where there are positive charges so they can interact.

45
Q

Foetal Hb binds O2 more strongly than adult Hb why?

A

Foetal HbF Adult HbA

HbF binds BPG less effectively, so has higher affinity for O2.
Allows efficient transfer of O2 across the placenta.

Foetal Hb has a gamma subunit. The gamma subunit alters the affinity of Hb for oxygen.

46
Q

Haemoglobinopathies and examples

A

A range of inherited disorders affecting haemoglobin synthesis, structure and function.

E.g. sickle cell anaemia and Beta- thalassaemia

47
Q

Critical amino acid residues

A

His- Role is proximal His and Distal His
Phe and Leu-Role- Haem contact- involved in hydrophobic pocket in haem. Removal of this amino acid. Haem falls out of Hb.
Gly- Role-B and E helices contact- any other amino acid there is less contact
Pro- Helix termination- side chain loops round and covalently bonds to the N on the amino group. Proline can’t HB to alpha helix.
Tyr- H-bonds between H and F helices

48
Q

Conservative substitution

A

Substitute one amino acid for something very similar

49
Q

Non-conservative substitution

A

Substitution of one amino acid that is very different

50
Q

Which of the following is a positively charged amino acid?

A

Arginine

51
Q

Which of the following is a negatively charged amino acid?

A

Glutamate

52
Q

Which amino acid does not have optical activity?

A

Glycine

53
Q

Which of these amino acids would you expect to find in the centre of a protein molecule?

A

Valine because it is hydrophobic

54
Q

Disulphide bonds are formed between pairs of which amino acid

A

Cystine (to form cysteine)

55
Q

Why is binding of oxygen to haemoglobin said to be cooperative?

A

The binding of one molecule of oxygen causes a structural change in the Hb that makes it easier for other molecules of oxygen to bind

56
Q

What is the effect of decreased pH on oxygen binding to Hb?

A

This lowers the affinity of Hb for oxygen, so the oxygen is released in tissues that are producing lactic acid or have high CO2 levels.

57
Q

Why does bisphosphoglycerate concentration in red blood cells increase at high altitude?

A

BPG reduces oxygen affinity to Hb. At high altitude there is less oxygen available, so it is better for the Hb to release the oxygen in tissues that are low in oxygen.

58
Q

What is collagen?

A
  • Structural protein
  • Family of fibrous proteins
  • Forms insoluble fibres, high tensile strength
  • Most abundant protein in mammals
  • Major fibrous element of skin, bone, tendon, cartilage, blood vessels and teeth
  • Present in most organs
  • Holds cells together in discrete units – basement membranes
  • Directive role in developing tissue
59
Q

Different types of collagen due to different polypeptide chains in tropocollagen?

A
  • Types I, II and III are the most common – form long fibrils (fibril-forming collagens)
  • Types IV & VII form 2-dimensional matrix – important in basal lamina (network-forming collagens)
  • Other collagen types are mainly associated with major forms, and may be involved in crosslinking e.g. types V, IX, XII (fibril-associated collagens)
60
Q

Biosynthesis of collagen

A

Biosynthesis of Collagen

  1. Post translational modifications (within fibroblast)
  2. Procollagen triple helical cable (within fibroblast)
  3. Secretion out of cell
  4. Removal of extension peptides (In extracellular spaces of connective tissue)
  5. Tropocollagen formed (In extracellular spaces of connective tissue)
  6. Aggregation into microfibril (In extracellular spaces of connective tissue)
  7. Cross linking to form collagen fibre (In extracellular spaces of connective tissue)
61
Q

Primary structure of collagen

A

Gly every third residue.

Repeating sequence:
(Gly – X – Y)n, X often Proline (Gly-Pro-Y), Y often Hydroxyproline
(Gly-X-Hyp). All Covalently modified amino acids.

Amino acid composition of collagen 33% Gly (in Hb 5%)

62
Q

Hydroxylation of proline and lysine residues process

A

Process occurs before the polypeptide chains form a helix.
Enzymes involved are prolyl hydroxylase and lysyl hydroxylase.
Both require ascorbic acid (vitamin C) as co-factor.

Hydroxyproline is involved in H-bond formation, which helps to stabilise the triple helix.

Hydroxylysine residues are attachment sites for sugar residues, and are involved in cross-linking between collagen chains.

63
Q

Secondary, tertiary and quaternary structure of collagen

A

Each polypeptide chain forms a LEFT handed helix.

These combine to form a triple helix formed (tropocollagen) RIGHT handed twist.

Pro and Hyp residues on the outside. Gly residues pack into the centre.

64
Q

Assembly of collagen

A
  • Collagen chains are synthesised with additional amino acids at each end – extension peptides
  • Assembly begins with disulphide bond formation between C-terminal extensions – facilitates triple helix assembly
  • Peptidase enzymes remove extension peptides after secretion into extracellular space
  • Tropocollagen spontaneously forms fibrils – stabilised by covalent cross-links
65
Q

What are collagenases?

A
  • Collagen is very stable but in some conditions collagen breakdown is necessary for growth, tissue remodelling (e.g. pregnancy/ after birth/ return of uterus after birth)
  • Tissue repair

Collagenase enzymes are therefore required – a family of metalloproteinases

Collagenases are important in tumour invasion and metastasis (spreading) – often produced at high levels by tumour cells.

Collagenases destroy the connective tissues around the tumour.

66
Q

Use of collagenases

A

Dupuytren’s contracture- A potentially disabling condition caused by excess collagen production affecting the connective tissue of the hand

67
Q

Diseases occur when collagen structure or synthesis is abnormal

A 
Osteogenesis Imperfecta (brittle bone disease)– mutation in collagen chains
Ehlers-Danlos syndrome type VI – Lysyl oxidase deficiency
Scurvy
68
Q

Ehlers-Danlos syndrome

A

Inherited disorders resulting from poorly formed/weak collagen in connective tissue (ligaments, tendons, blood vessels, internal organs)

69
Q

Osteogenesis imperfecta – ‘brittle bone disease’

A

A range of inherited disorders characterised by increased risk of bone fractures. It is caused by mutations in Type I collagen

70
Q

Which protein is defective in the following diseases

a) Ehlers-Danlos syndrome
b) Muscular dystrophy
c) Haemophilia A
d) Scurvy
e) Favism
f) Phenylketonurea

A

a) Ehlers-Danlos syndrome
b) Muscular dystrophy
c) Factor VIII
d) Collagen
e) Glucose 6-phosphate deydrogenase
f) Phenylalanine hydroxylase

IMS (13 decks)

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