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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
Describe RBCs
Like sacs of hemoglobin -no nuclei -no mitochondria -no other organelles
26
What is the structure of adult Hb?
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
27
How does fetal hemoglobin differ from adult Hb?
Fetal Hb has 2 alpha and 2 gamma chains
28
What is myoglobin?
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
29
What does oxygen bind to in Hb?
The iron at the center of a heme molecule and to a histidine side chain
30
What is the mechanism for myoglobin to bind oxygen?
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
31
How does the oxygen-Hb curve compare to that of myoglobin?
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%
32
What are the 2 Hb tetramer conformations?
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
33
What shifts the equilibrium b/w the theoretical T and R forms of Hb?
Binding of oxygen and some other small molecules
34
What is the Hb O2-binding curve relative to the theoretical T and R states?
The sum of the 2 state curves https://pdb101.rcsb.org/motm/41
35
When the [O2] is lower, what state will Hb be in?
More in the T-state T-low [O2] (tenor) R-high [O2]
36
As O2 binds, when does the R state predominate?
Once 2 O2 molecules have bound to 2 different subunits of Hb
37
Once 2 O2 molecules are bound to Hb subunits, what change in [O2] is needed to bind the 2 others?
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
What is the term to describe the Hb O2 binding?
cooperativity
39
What forms when O2 is not bound (and in the T state)?
4 stabilizing ion pairs (one in each subunit) b/w the F8 helix's Asp-94 and His-146
40
What happens on the molecular level when O2 binds Hb?
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
What happens on the molecular level when 2+ O2 molecules bind to Hb?
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
What compounds influence the Hb-O2 binding curve to increase the delivery of O2?
CO2 protons, H+ 2,3-BPG (bisphosphoglycerate)
43
How do CO2, H+ and 2,3-BPG influence O2 delivery?
They all stabilize the T-state confirmation, which promotes O2 release
44
How do CO2, H+ and 2,3-BPG act on Hb?
They are allosteric regulators b/c they bind Hb somewhere other than the O2 binding site and affect its affinity for O2
45
What is Hb called when CO2 is covalently attached?
Carbaminohemoglobin
46
What happens when CO2 binds Hb?
~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
What is the Bohr effect?
Protonation of Hb -an increase in [H+] stabilize the T-state -> increased O2 delivery
48
Why do cells and tissues need more O2 with increased [H+]?
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
What is 2,3-BPG?
A small metabolite, made in RBCs from a side path off glycolysis
50
How does 2,3-BPG effect Hb on the molecular level?
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
What controls levels of 2,3-BPG?
Strictly controlled in RBCs so it can be released quickly to increase O2 delivery to tissues, for example when going to high altitude
52
What are 3 pathologic states of Hb?
1. Carboxyhemoglobin 2. methemoglobin 3. Sickle cell variant (one of many Hb variants)
53
What is carboxyhemoglobin?
When carbon monoxide (CO) binds to Hb
54
What does CO bind to in addition to binding Hb?
Complex IV of the ETC in mitochondria
55
When is CO produced?
It's constantly produced during RBC turnover (heme catabolism)
56
What percentage of Hb is always bound to CO?
<3% in non-smokers and <10% in people who smoke
57
What does CO do when it binds Hb?
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
At what percentage of binding does CO cause tissue function impairment?
When >15%-20% of hemoglobin is bound to CO
59
What is methemoglobin?
When iron in the center of the heme becomes oxidized (loss of electrons) from Fe2+ (normal state) to Fe3+ (methemoglobin)
60
What happens when methemoglobin forms?
O2 cannot bind
61
What causes methemoglobin formation?
A small amount is produced as normal part of RBC metabolism -more produced w/ congenital methemoglobinemia or exogenous oxidizing chemicals
62
What is the sickle cell variant of Hb?
The 6th codon of beta-globin is changed from a negatively-charged, hydrophilic glutamate to a hydrophobic valine
63
What happens when someone inherits 2 copies of the beta-globin gene with the sickle cell variant?
The adult form of their Hb, HbS, can polymerize into rigid fibrils when in the deoxygenated, T-state
64
What happens with sickle cell disease?
Causes painful vaso-occlusive crises, affecting organs and shortens life
65
What are current therapies for sickle cell disease?
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
What are 2 similarities b/w sickle cell disease and amyloid diseases?
1. both are diseases of protein folding 2. each is a specific type of protein aggregation
67
What are 3 differences b/w sickle cell disease and amyloid diseases?
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
What are proteins?
linear chains of AA, with a carboxyl group (COO-) and amino group (NH3+)
69
How is the sequence of a protein determined and formed?
Determined from mRNA (transcribed from DNA) and formed when the ribosome covalently attaches one AA to another
70
What does the AA sequence in a protein determine?
The structure and therefore the function of the protein
71
How are protein sequences read?
from the N (amino group) to C (carboxyl group)
72
How is a variant that results in an AA change written?
Asp163Val or D163V to describe the replacement of the 163rd AA, aspartic acid, with a valine
73
How many different AA are commonly found in proteins?
20
74
At the intracellular neutral pH of ~7, how many AA are ionic (charged) vs uncharged?
5 AA are ionic and carry a charge 15 are uncharged and either polar (hydrophilic) or non-polar (hydrophobic)
75
What are the essential AA?
threonine valine leucine isoleucine methionine phenylalanine tryptophan histidine lysine
76
What AA are hydrophobic?
valine leucine isoleucine methionine proline phenylalanine tyrosine tryptophan
77
What forces drive protein folding?
noncovalent forces, which are typically weak
78
How do systems change to affect their free energy?
They change to minimize their total free energy (deltaG) -reductions in deltaH (enthalpy) or increases in deltaS (entropy) will drive a rxn forward
79
What types of noncovalent forces favor protein folding?
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
What are 2 noncovalent forces that must be overcome for a protein to fold?
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
From the perspective of energy, when do proteins fold?
When the net energetic contributions of interactions in the folded protein are more favorable than those of the unfolded protein (when deltaG<0)
82
What are secondary protein structures?
Regular arrangements of the polypeptide backbone that are stabilized by H+ bonding b/w peptide amide and carbonyl groups
83
What are alpha helices?
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
What are beta-sheets?
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
What are secondary protein structural turns?
Peptide chains can reverse direction sharply -turns usually consist of hydrophilic residues, prolines and glycines
86
What is the role of water in proteins?
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
How are globular domains created?
By combining different secondary structural elements
88
What are domains, as related to proteins?
Semi-independent units (each usually has a distinct function) within a single protein that are contiguous portions of the folded polypeptide chain
89
What are protein tertiary structures?
The final arrangement of domains (w/ distinct functions) w/in a folded protein

MCC (44 decks)

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