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MCC > Wk 1 Protein & Hemoglobin Structure > Flashcards

Wk 1 Protein & Hemoglobin Structure Flashcards

1
Q

What do all genetic diseases, including cancer and likely almost all other diseases result from?

A

Improper protein amount, location, structure or function

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2
Q

What determines the folded structure of a protein?

A

The sequence of AA, which therefore also determines its function

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3
Q

Where do many proteins fold spontaneously?

A

In the cytosol as they emerge from the ribosome

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4
Q

What is the primary protein structure?

A

The linear chain of AA

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5
Q

What are the secondary protein structures?

A

alpha helices and beta sheets

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6
Q

What are the tertiary protein structures?

A

3D groupings of alpha-helices and beta-sheets

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7
Q

What are the quaternary protein structures?

A

3D polypeptides that interact with each other

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8
Q

What is a typical protein structure?

A

hydrophobic core w/ hydrophilic surface molecules

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9
Q

What is the typical structure of a transmembrane protein?

A

hydrophobic helices of ~20-25 AA buried in the lipid bilayer, connected together by loops and folded domains w/ polar atoms exposed to aqueous environment

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10
Q

What can cause protein aggregates?

A

inappropriate hydrophobic interactions b/w unfolded proteins in the cytosol

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11
Q

What are chaparones?

A

molecules that facilitate protein folding by inhibiting inappropriate interactions
-many are induced during stress (e.g. stress) and are called heat shock proteins

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12
Q

What relationship has been shown b/w Alzheimers and Parkinsons in some epidemiologic studies?

A

An inverse association b/w cancer and protein misfolding diseases (Alzheimers and Parkinsons): people who get cancer have a lower risk for the others

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13
Q

What is amyloid?

A

A specific type of aggregated protein structure
-can occur in almost every protein sequence

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14
Q

What are 6 diseases associated with amyloid?

A
  1. Alzheimers
  2. Parkinsons
  3. Huntington disease
  4. Systemic AL amyloidosis
  5. Familial amyloid polyneuropathy
  6. Prion diseases
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15
Q

What protein is involved in amyloid structure in Alzheimers?

A

beta-amyloid and Tau

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16
Q

What protein is involved in amyloid structure in Parkinsons?

A

alpha-synuclein

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17
Q

What protein is involved in amyloid structure in Huntington disease?

A

Huntingtin

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18
Q

What protein is involved in amyloid structure in systemic AL amyloidosis?

A

Immunoglobulin light chain

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19
Q

What protein is involved in amyloid structure in familial amyloid polyneuropathy?

A

Transthyretin

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20
Q

What protein is involved in amyloid structure in prion disease?

A

prion protein (PrP)

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21
Q

How does amyloid appear with stained w/ Congo red and observed under polarized light?

A

apple green color

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22
Q

What is prion disease?

A

A rare, fatal neurodegenerative disease caused by misfolding of the prion protein (PrP).
-most cases are spontaneous, 15% are genetic, small % due to infection

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23
Q

What happens in prion disease to cause it?

A

The prion protein is usually a normal cellular protein mostly expressed w/in the nervous system. Native form mostly alpha-helical.
-same pro sequence can be induced -> beta-sheet structure called the scrapie, which -> amyloid fibrils that damage or destroy neurons, leaving sponge-like holes in the brain

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24
Q

What is the role of hemoglobin?

A

To bind and release oxygen so tissues receive adequate but not excessive oxygen

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25
Q

Describe RBCs

A

Like sacs of hemoglobin
-no nuclei
-no mitochondria
-no other organelles

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26
Q

What is the structure of adult Hb?

A

4 subunits:
2 alpha polypeptide chains
2 beta polypeptide chains
-each chain binds a heme group w/ an iron atom in the center
-oxygen binds to the iron of the heme

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27
Q

How does fetal hemoglobin differ from adult Hb?

A

Fetal Hb has 2 alpha and 2 gamma chains

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28
Q

What is myoglobin?

A

A single chain protein (monomer) within the cytoplasm of muscle cells.
-temporarily stores oxygen and rapidly delivers it to mitochondria as energy demands increase
-similar to a beta chain

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29
Q

What does oxygen bind to in Hb?

A

The iron at the center of a heme molecule and to a histidine side chain

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30
Q

What is the mechanism for myoglobin to bind oxygen?

A

A simple mechanism w/o conformational changes, just binding and releasing oxygen
-90% will be bound to oxygen at 20 mm Hg and then only 10% at 10 mm Hg to help prevent tissue damage
-has a high affinity for oxygen, so after releasing it, high probability of re-binding more

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31
Q

How does the oxygen-Hb curve compare to that of myoglobin?

A

The O2-Hb mechanism: a decrease of only 5-fold in [O2] (compared to 81-fold for myoglobin) -> a change from 90% Hb bound to O2 down to 10%

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32
Q

What are the 2 Hb tetramer conformations?

A
  1. R = relaxed form, which has a high affinity for oxygen
  2. T = taut form, which has a low affinity for oxygen
    -the Hb polypeptides have similar structures in each form, but the orientation of the subunits to each other shifts
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33
Q

What shifts the equilibrium b/w the theoretical T and R forms of Hb?

A

Binding of oxygen and some other small molecules

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34
Q

What is the Hb O2-binding curve relative to the theoretical T and R states?

A

The sum of the 2 state curves
https://pdb101.rcsb.org/motm/41

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35
Q

When the [O2] is lower, what state will Hb be in?

A

More in the T-state
T-low [O2] (tenor)
R-high [O2]

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36
Q

As O2 binds, when does the R state predominate?

A

Once 2 O2 molecules have bound to 2 different subunits of Hb

37
Q

Once 2 O2 molecules are bound to Hb subunits, what change in [O2] is needed to bind the 2 others?

A

Very small increase in [O2]
-this is the same in reverse. A small decrease in [O2] b/w that in the lung capillaries and tissue capillaries will shift from R state to T state, releasing O2 for tissues to use

38
Q

What is the term to describe the Hb O2 binding?

A

cooperativity

39
Q

What forms when O2 is not bound (and in the T state)?

A

4 stabilizing ion pairs (one in each subunit) b/w the F8 helix’s Asp-94 and His-146

40
Q

What happens on the molecular level when O2 binds Hb?

A

O2 binds to an iron (Fe2+) molecule, pulling it and the F8 molecule to the side, breaking the ion bond and increasing the free energy of Hb, decreasing the probability of this occurring b/c Hb is more stable w/o O2 bound compared to one molecule bound

41
Q

What happens on the molecular level when 2+ O2 molecules bind to Hb?

A

R-state is favored and all 4 Asp-94-His-146 ion pairs are broken -> O2 affinity is high at all 4 sites, almost all or nothing for O2 binding = cooperativity

42
Q

What compounds influence the Hb-O2 binding curve to increase the delivery of O2?

A

CO2
protons, H+
2,3-BPG (bisphosphoglycerate)

43
Q

How do CO2, H+ and 2,3-BPG influence O2 delivery?

A

They all stabilize the T-state confirmation, which promotes O2 release

44
Q

How do CO2, H+ and 2,3-BPG act on Hb?

A

They are allosteric regulators b/c they bind Hb somewhere other than the O2 binding site and affect its affinity for O2

45
Q

What is Hb called when CO2 is covalently attached?

A

Carbaminohemoglobin

46
Q

What happens when CO2 binds Hb?

A

~10% of CO2 produced by metabolism reacts w/ terminal amino end of each Hb chain, making them (-) charged, which then interact w/ (+) amino acids that are positioned for an ion pair in the T-state. So, increased CO2 in tissues stabilizes T-state and increased O2 release

47
Q

What is the Bohr effect?

A

Protonation of Hb
-an increase in [H+] stabilize the T-state -> increased O2 delivery

48
Q

Why do cells and tissues need more O2 with increased [H+]?

A
  1. w/ insufficient O2, cells produce more lactate via anaerobic glycolysis, which leaves the cell w/ a H+, favoring the T state locally
  2. In actively metabolizing cells, CO2 is produced, which is converted to carbonic acid and then bicarbonate and H+ -> increased [H+] -> increased O2 delivery
49
Q

What is 2,3-BPG?

A

A small metabolite, made in RBCs from a side path off glycolysis

50
Q

How does 2,3-BPG effect Hb on the molecular level?

A

It fits in the central hole of the T-state structure, not the R-state, thereby stabilizing the T-state and increasing O2 delivery

51
Q

What controls levels of 2,3-BPG?

A

Strictly controlled in RBCs so it can be released quickly to increase O2 delivery to tissues, for example when going to high altitude

52
Q

What are 3 pathologic states of Hb?

A
  1. Carboxyhemoglobin
  2. methemoglobin
  3. Sickle cell variant (one of many Hb variants)
53
Q

What is carboxyhemoglobin?

A

When carbon monoxide (CO) binds to Hb

54
Q

What does CO bind to in addition to binding Hb?

A

Complex IV of the ETC in mitochondria

55
Q

When is CO produced?

A

It’s constantly produced during RBC turnover (heme catabolism)

56
Q

What percentage of Hb is always bound to CO?

A

<3% in non-smokers and <10% in people who smoke

57
Q

What does CO do when it binds Hb?

A

It’s a pollutant and poison (in addition to being a product of heme catabolism) that stabilizes the R-state structure, causing a left shift in the O2-binding curve, preventing the release of O2 to tissues

58
Q

At what percentage of binding does CO cause tissue function impairment?

A

When >15%-20% of hemoglobin is bound to CO

59
Q

What is methemoglobin?

A

When iron in the center of the heme becomes oxidized (loss of electrons) from Fe2+ (normal state) to Fe3+ (methemoglobin)

60
Q

What happens when methemoglobin forms?

A

O2 cannot bind

61
Q

What causes methemoglobin formation?

A

A small amount is produced as normal part of RBC metabolism
-more produced w/ congenital methemoglobinemia or exogenous oxidizing chemicals

62
Q

What is the sickle cell variant of Hb?

A

The 6th codon of beta-globin is changed from a negatively-charged, hydrophilic glutamate to a hydrophobic valine

63
Q

What happens when someone inherits 2 copies of the beta-globin gene with the sickle cell variant?

A

The adult form of their Hb, HbS, can polymerize into rigid fibrils when in the deoxygenated, T-state

64
Q

What happens with sickle cell disease?

A

Causes painful vaso-occlusive crises, affecting organs and shortens life

65
Q

What are current therapies for sickle cell disease?

A
  1. hydroxyurea - induces expression of the fetal gamma-globin and blocks polymerization of HbS
  2. L-glutamine, which induces production of NADPH to help prevent hemolysis
  3. BM transplant
  4. CRISPR-Cas9 gene editing is a promising experimental therapy
66
Q

What are 2 similarities b/w sickle cell disease and amyloid diseases?

A
  1. both are diseases of protein folding
  2. each is a specific type of protein aggregation
67
Q

What are 3 differences b/w sickle cell disease and amyloid diseases?

A
  1. each HbS tetramer maintains alpha-helical fold and native structure vs amyloid formation involves polymerization of beta-sheets from misfolded or unfolded proteins
  2. HbS polymerization is specific for variants of beta-globin (most commonly G6V) vs amyloid can form from many diff proteins, unmutated and mutated
  3. HbS polymerization well understood vs amyloid role in diseases mysetery
68
Q

What are proteins?

A

linear chains of AA, with a carboxyl group (COO-) and amino group (NH3+)

69
Q

How is the sequence of a protein determined and formed?

A

Determined from mRNA (transcribed from DNA) and formed when the ribosome covalently attaches one AA to another

70
Q

What does the AA sequence in a protein determine?

A

The structure and therefore the function of the protein

71
Q

How are protein sequences read?

A

from the N (amino group) to C (carboxyl group)

72
Q

How is a variant that results in an AA change written?

A

Asp163Val or D163V to describe the replacement of the 163rd AA, aspartic acid, with a valine

73
Q

How many different AA are commonly found in proteins?

A

20

74
Q

At the intracellular neutral pH of ~7, how many AA are ionic (charged) vs uncharged?

A

5 AA are ionic and carry a charge
15 are uncharged and either polar (hydrophilic) or non-polar (hydrophobic)

75
Q

What are the essential AA?

A

threonine
valine
leucine
isoleucine
methionine
phenylalanine
tryptophan
histidine
lysine

76
Q

What AA are hydrophobic?

A

valine
leucine
isoleucine
methionine
proline
phenylalanine
tyrosine
tryptophan

77
Q

What forces drive protein folding?

A

noncovalent forces, which are typically weak

78
Q

How do systems change to affect their free energy?

A

They change to minimize their total free energy (deltaG)
-reductions in deltaH (enthalpy) or increases in deltaS (entropy) will drive a rxn forward

79
Q

What types of noncovalent forces favor protein folding?

A
  1. hydrogen bonds: partial sharing of a H+ b/w 2 electronegative groups (nitrogen and O2)
  2. Burying hydrophobic groups w/in protein is energetically favorable
  3. Ionic/eletrostatic interactions b/w (+) and (-) charged groups play role in cooperativity and O2 release
80
Q

What are 2 noncovalent forces that must be overcome for a protein to fold?

A
  1. enthalpic forces -unfolded polypeptides can make enthalpically favorable interactions w/ solvent (eg H-bonds w/ water), which must be overcome
  2. entropic forces - folding is entropically unfavorable for the protein b/c conformational freedom is decreased
81
Q

From the perspective of energy, when do proteins fold?

A

When the net energetic contributions of interactions in the folded protein are more favorable than those of the unfolded protein (when deltaG<0)

82
Q

What are secondary protein structures?

A

Regular arrangements of the polypeptide backbone that are stabilized by H+ bonding b/w peptide amide and carbonyl groups

83
Q

What are alpha helices?

A

3.6 AA/turn
-carbonyl group of AA n hydrogen bonds w/ the amide of amino acid n+3
-typical helix is ~10-14 AA
-often amphipathetic (have hydrophobic and hydrophilic sides)
-prolines break alpha helices so a missense variant that inserts a proline can -> protein misfolding

84
Q

What are beta-sheets?

A

Adjacent polypeptide chains associate by hydrogen bonding in sheet-like structures
-the beta-strands within a sheet can be anti-parallel (most stable), parallel or mixed

85
Q

What are secondary protein structural turns?

A

Peptide chains can reverse direction sharply
-turns usually consist of hydrophilic residues, prolines and glycines

86
Q

What is the role of water in proteins?

A

Proteins are covered by water molecules that hydrogen bond to exposed polar side chains and stabilize the ends of secondary structures
-also w/in catalytic sites of enzymes where they influence substrate binding

87
Q

How are globular domains created?

A

By combining different secondary structural elements

88
Q

What are domains, as related to proteins?

A

Semi-independent units (each usually has a distinct function) within a single protein that are contiguous portions of the folded polypeptide chain

89
Q

What are protein tertiary structures?

A

The final arrangement of domains (w/ distinct functions) w/in a folded protein

MCC (44 decks)

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