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CHE 4341 Baylor (Dr. Jonklaas) > Biochem Exam 2 > Flashcards

Biochem Exam 2 Flashcards

1
Q

What is the primary structure of a protein?

A

Amino Acid sequence and location of S-S bonds

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2
Q

What is the main bonding interactions for primary structures?

A

Covalent Bonds

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3
Q

What kind of covalent bonds are found in proteins?

A

Amide bonds and disulfide bonds

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4
Q

What is secondary protein structure?

A

Interaction of amino acids close to each other to form specific patterns

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5
Q

What is the main bonding interaction for secondary protein structure?

A

Hydrogen bonds

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6
Q

What is the main bonding interaction for tertiary strucutre?

A

Hydrophobic effect

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7
Q

What is Quaternary Structure?

A

Arrangement of multiple folded protein molecules (subunits) in a multi-subunit protein.

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8
Q

What is the main bonding interaction in forming quaternary structure?

A

Hydrophobic effect

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9
Q

Are there usually disulfide bonds or covalent bonds between subunits?

A

No

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10
Q

What percent Double Bond are peptide bonds? What does this make them?

A

40% double bond character makes them planar

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11
Q

Are peptide bonds usually cis or trans?

A

Trans

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12
Q

Can you rotate around a peptide bond?

A

No

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13
Q

Who discovered the nature of the peptide bond?

A

Pauling and Corey

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14
Q

Where can you rotate bonds in the protein chain?

A

Around the alpha carbon

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15
Q

What are the angles on either side of the alpha carbon called?

A

Phi an psi angles

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16
Q

What is the angle of the phi and psi bonds in a fully extended chain?

A

Close to +/- 180°

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17
Q

Why are certain values of phi and psi forbidden?

A

Certain values are forbidden because of steric hindrance

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18
Q

What is a Ramachandran plot?

A

Calculated plot of all sterically allowed psi and phi angles for a polypeptide chain

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19
Q

What does the green space on the Ramachandran plot represent?

A

Angles of phi and psi where Glycine is present

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20
Q

What does the blue space represent on the Ramachandran plot?

A

The angles of phi and psi for the other 19 amino acids

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21
Q

What is the definition of secondary structure?

A

The general 3D form of local segments or biopolymers such as proteins and nucleic acids (DNA/RNA) to give regular, recurring local conformations

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22
Q

What are general secondary structures in proteins?

A

alpha helix, beta strand, beta bend, collagen triple helix, loops & turns

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23
Q

What do the Hydrogen bonds occur between in protein secondary structure?

A

backbone amide NH of one Amino Acid and backbone carbonyl C=O of another

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24
Q

Who proposed the alpha helix?

A

Linus Pauling

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25
Q

Which residues does hydrogen bonding occur between?

A

n and n+4 residues

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26
Q

What residues bind in a 3-10 helix?

A

n and n+3

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27
Q

Who are considered the founders of structural biology?

A

Linus Pauling & Robert Corey

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28
Q

Which way do R groups point in alpha helix structures?

A

R groups point outwards, perpendicular to axis

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29
Q

Describe the orientation of Hydrogen bonds relative to the alpha helix

A

H-bonds are parallel to helix axis

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30
Q

What is the pitch on an alpha helix?

A

5.4 angstroms

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31
Q

How many residues does it take to make one turn of the alpha helix?

A

3.6 residues per turn

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32
Q

What is the rise of the alpha helix?

A

1.5 angstroms

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33
Q

Are alpha helices in nature right or left handed?

A

Right handed

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34
Q

Does an alpha helix have a dipole? Why?

A

Yes, alpha helices have dipoles. This is because all C=O groups point towareds the C-terminus, giving entire helix a dipole with (+) N, (-) C-termini

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35
Q

Do stable alpha helices typically end with a (+) or a (-) charged amino acid? Why?

A

Stable alpha helices typically end (C-term) with a (+) charged AA to neutralize the dipole moment.

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36
Q

Is proline found in alpha helices? Why?

A

Proline is not likely found in alpha helices because its cyclic side chain sterically destabilizes an alpha helix

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37
Q

What causes steric repulsion in alpha helices?

A

Steric (/charge) repulsion by adjacent bulky (/like-charged) amino acids

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38
Q

Which AAs are too large to be found in alpha helices?

A

Tryptophan and Tyrosine

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39
Q

Which AAs are too small to be found in alpha helices?

A

Glycine

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40
Q

Can alpha helices be amphipathic? What doe this mean?

A

Alpha helices can be amphipathic - This means that hydrophobic resides on one side and hydrophilic residues on opposite side

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41
Q

What is alpha-Keratin?

A

A coiled-coil motif

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42
Q

What is alpha-keratin made up of?

A

Amphipathic alpha helices

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43
Q

Where is alpha-Keratin commonly found?

A

Hair, skin, and nails

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44
Q

What is alpha Keratin rich in? Why is this signficant?

A

Alpha-Keratin is rich in Cysteine, which is important because Cys forms -S-S- bonds

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45
Q

What is the biochemistry behind getting a perm?

A

Heat reduces -S-S- bonds, which breaks linkages; Next, curl; Then re-oxidize to form -S-S- bonds; This holds hair in new position

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46
Q

What can alpha keratin be used to detect? Why does this work?

A

Alpha-keratin can be used to detect heavy metal poisoning. This is because Cys attracts strong metals.

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47
Q

What are Beta Stands

A

Secondary structure in which polypeptide strands are almost fully extended

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48
Q

How many B strands are in B sheets?

A

At least two Beta strands are required to make a Beta sheet

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49
Q

Where can strands in Beta sheets come from?

A

Stands can come from same polypeptide, completely different sections of a polypeptide, or even different polypeptides.

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50
Q

What plane are strands in in Beta sheets?

A

Strands are in X-plane

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51
Q

Where are H-bonds oriented in Beta sheets?

A

H-bonds occur between amino acids on adjacent strands, perpendicular (Y direction) to strand direction

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52
Q

Where are R groups oriented in Beta strands?

A

Side chains (R-groups) alternate in pointing above and below plane, perpendicular to H-bonds AND strands (Z plane)

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53
Q

Why can Beta sheets accomodate more bulky substituents?

A

Because the R groups alternate in pointing above and below the plane of the sheets. This limits adjacent bulky/like charged residues.

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54
Q

What is the difference between parallel and antiparallel Beta sheets?

A

In Antiparallel sheets, strands run in opposite N- to C-terminal direction, while in Parallel sheets, strands run in the same N- to C- direction

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55
Q

Is Anti-parallel or parallel Beta sheets stronger?

A

Antiparallel are stronger because they give you linear H-bonds

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56
Q

What is the general overall structure of a Beta strand?

A

Extended zig-zag (ruffled) conformation

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57
Q

How many residues are involved per strand in Beta sheets?

A

6-12 residues involved per strand

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58
Q

What is the order of AAs pattern in Beta Sheets?

A

Repeating units of 2 AA residues with distance = 7 angstroms (3.5 A per AA)

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59
Q

Can Beta sheets be amphipathic?

A

Yes; One surface of Beta sheet may consist of hydrophobic side chains (R grps) while other can have hydrophilic ones

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60
Q

Do Beta strands in a Beta sheet twist?

A

Yes, Beta strands can twist

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61
Q

Can some proteins be all Beta sheets?

A

Yes

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62
Q

What is an example of Beta Sheets in nature?

A

Spider’s silk

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63
Q

What makes spider silk so strong?

A

Extended layers of antiparallel Beta Sheets

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64
Q

What is the AA pattern in spider silk?

A

(-Gly-Ser-Gly-Ala-Gly-Ala-) - Alanine from 1 sheet interdigititates with Alanine from another sheet.

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65
Q

What is collagen notably used for?

A

Collagen is the main structural protein in the extracellular matrix (ECM) in connective tissue in animals

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66
Q

What percentage of protein mass in large animals is made up of collagen?

A

Roughly 1/3rd of the total protein mass

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67
Q

What is collagen present in?

A

Bone matrix, tendons, cartilage, blood vessels, skin, etc.

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68
Q

What form is collagen?

A

Triple helix

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69
Q

Which AA is found abundantly in the collagen triple helix?

A

Proline

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70
Q

What is the general repeating AA pattern of the collagen triple helix?

A

G-P-P/Hyp

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71
Q

What residue is invariant in the collagen triple helix?

A

Glycine - It is located along central axis of triple helix (other residues cannot fit)

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72
Q

Where is H-bonding located in collagen triple helix? What residues does it bind between?

A

H-bonding is interchain and occurs between amide NH of one helix to carbonyl oxygens of another helix

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73
Q

Are there any intrachain H-bonds in collagen triple helix?

A

No

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74
Q

What is the cause of one type of Osteogenesis Imperfecta?

A

Occurs when a mutation in a gene for collagen leads to the substitution of Glycine for another amino acid. This prevents the normal production of mature collagen, which leads to brittle bones.

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75
Q

What structure is this?

A

Ascorbic Acid (Vitamin C)

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76
Q

How does Vitamin C help with building the collagen triple helix?

A

Formation of HydroxyPro and HydroxyLys requires oxygen and vitamin C

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77
Q

What is a vitamin C deficiency called?

A

Scurvy

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78
Q

What are the effects of scurvy?

A

Scurvy results in a lack of hydroxyPro, which leads to weak collagen (skin lesions, fragile blood vessels, bleeding gums)

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79
Q

What are collagen fibrils strengthened by?

A

Intrachain lysine-lysine and interchain hydroxypyridinium covalent crosslinks

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80
Q

What are the effects of collagen cross-links as they accumulate over time?

A

Increase in cross-links lead to less elastic collagen, which leads to more brittle bones/tendons (many of the signs of old age)

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81
Q

What kind of secondary structures are loops and turns?

A

Non-regular secondary structures

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82
Q

What do turns allow?

A

Turns and loops allow chain reversal

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83
Q

Where are loops are turns found?

A

Normally on surface of globular proteins (hydrophilic)

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84
Q

What does the Beta turn allow?

A

Allows polypeptide in antiparallel Beta sheet to reverse direction

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85
Q

What residues are bonded in a Beta turn?

A

Carbonyl O’s are H-bonded to amide H’s between residues 1 and 4

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86
Q

Which amino acid helps make the tight, rigid turn as the 2nd residue in the turn?

A

Proline

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87
Q

Where are Beta sheets found in the Ramachandran plot? Why?

A

Beta sheets are found in the top left corner of the Ramachandran plot, because Beta sheets have elongated strands, so phi and psi angles are close to 180°

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88
Q

What is tertiary structure? What causes tertiary structure to form?

A

Tertiary structure results from the folding of a polypeptide chain into a closely-packed 3D structure, mainly because of hydrophobic effect

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89
Q

What is one effect of tertiary structure?

A

Amino acids far apart in the primary structure may be brought closer together

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90
Q

What does X-ray crystallography do?

A

Reveals 3D structure in atomic detail

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91
Q

What do you need to perform x-ray crystallography?

A

Crystals of the protein (difficult to obtain)

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92
Q

What is one caveat with x-ray crystallography?

A

It gives a frozen picture of proteins (when they are “alive”, proteins move)

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93
Q

What are the steps to calculating protein structure from the diffraction pattern of x-ray crystallography?

A
  1. Obtain diffraction pattern
  2. Fourier Transform
  3. Computer fit map to protein sequence
  4. Fixed (frozen) picture of protein
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94
Q

Why is X-ray crystallography difficult to perform for many proteins?

A

You have to have protein crystals, which are very difficult to get for many proteins

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95
Q

What new technique can be used to visualize proteins in solution?

A

2D NOESY NMR Spectroscopy

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96
Q

What are 3 limitations of the NOESY technique for visualizing proteins?

A
  1. Need high concentrations of protein
  2. Time consuming
  3. Only works for small proteins
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97
Q

What does it mean for proteins to be “dynamic” in solution?

A

Their structure can be displaced up to 2 angstroms

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98
Q

What is Cryo-Electron Microscopy? (CEM)

A

Form of transmission electron microscopy (TEM) where the sample is studied at cryogenic temperatures

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99
Q

What do you do with a protein structure once you have determined it?

A

Add it to a protein data bank

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100
Q

What is the difference between globular proteins and fibrous proteins?

A

Globular proteins are water soluble, while fibrous proteins are normally insoluble

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101
Q

What causes proteins to denature?

A

Heat

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102
Q

Can all proteins be refolded?

A

No

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103
Q

What happens to proteins that unfold within a cell? What molecule carries this action out?

A

They are tagged for destruction by Ubiquitin

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104
Q

What is the name of the complex that “shreds” proteins?

A

26s Proteosome

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105
Q

What is the term for protein degredation?

A

Proteolysis

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106
Q

What are chaotropic reagents? What do they do? How do they work?

A

Proteins are denatured by Chaotropic agents; They work by disrupting interactions that stabilize tertiary structure

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107
Q

Who is Christian Anfinsen? What is he known for? Describe his experiment.

A

Anfinsen is known for discovering that primary structure determines tertiary structure. He did this by using 8 M Urea and mercaptoethanol to denature RNase A (a protein that does refold, luckily). Whenever he dialyzed out Urea and Mercaptoethanol, the protein refolded, because the primary structure was still in tact.

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108
Q

What groundbreaking discovery did Christian Anfinsen make?

A

He showed the primary structure determines tertiary structure

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109
Q

What determines the tertiary structure in proteins?

A

Primary structure

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110
Q

What are the interactions that help maintain tertiary structure? (5)

A

Hydrophobic effect, ionic interaction, metal ion coordination, hydrogen bonds, and disulfide bridges

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111
Q

What factors of protein folding are (-) deltaG (favorable)? What about (+) deltaG (unfavorable)?

A

The internal reactions involving deltaH (enthalpy) are favorable, along with the deltaS (entropy) of the water molecules in the hydrophobic effect ….. deltaS (entropy) of the folded protein is unfavorable.

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112
Q

What must be overcome for proteins to fold? (energetics)

A

The large decrease in entropy (deltaS) of the folding protein

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113
Q

How long does it take for most proteins to fold?

A

Less than 10 seconds

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114
Q

What does Levinthal’s Paradox state?

A

Protein DON’T sample all possible folding conformation & must only sample through limited conformations, & thus fold be “specific pathways”

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115
Q

What is the order of steps in which proteins fold in the accepted model of protein folding?

A
  1. The protein collapses in upon itself due to hydrophobic effect
  2. Secondary structures quickly form
  3. Then, the tertiary structure begins to form
  4. Finally, the native state forms
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116
Q

What is a protein folding funnel?

A

Energy landscape that guides protein towards native state

117
Q

What is the native state? Why is this significant?

A

The native state is the global minimum (most stable conformation) of a protein ….. Sometimes proteins can get stuck at a local minimum, which can cause disease

118
Q

Is it more difficult to fold proteins in vitro or in vivo? Why?

A

It is more difficult to fold proteins in vivo because the cellular environment is crowded, creating a high potential for misfolding and precipitation

119
Q

What are Chaperones? Do all proteins need chaperones?

A

Chaperones are proteins that help other proteins fold in vivo; Most proteins can fold without chaperones

120
Q

What is another name for Chaperones?

A

Heat Shock Proteins (HSPs)

121
Q

Does protein folding require energy?

A

Yes

122
Q

What is the role of DNAJ and DNAK in protein folding?

A

Precipitation is prevented (/folding assisted) by DNAJ & DNAK coating the unfolding protein and preventing denaturation

123
Q

What is a common, large Chaperone? What is another name for this molecule? What subunits is it made up of?

A

Chaperonins (also called GroEL/GroES complex) … made up of these subunits (GroES is the “cap” and GroEL is the “barrel”)

124
Q

Where does energy required for protein folding come from?

A

ATP hydrolysis

125
Q

What is the role of protein disulfide isomerases in protein folding?

A

Protein disulfide isomerases facilitate the formation of correct disulfide bridges

126
Q

What is the role of peptidyl proline isomerase in protein folding?

A

Peptidyl proline isomerases catalyze cis-trans isomerisation of peptide bonds involving proline

127
Q

What happens to misfolded proteins?

A

Misfolded proteins either refold and get proteolyzed immediatley

128
Q

What happens when misfolded proteins are not immediately refolded or proteolyzed?

A

The can accumulate as precipitates, which can result in sever, chronic degenerative diseases that affect the brain and Central Nervous System

129
Q

What is the general cause of diseases that have to do with protein misfolding?

A

Disease often occurs when a soluble protein with a mostly alpha-helix conformation misfolds into a Beta sheet conformation (forms a common cross-beta helical core filament structure)

130
Q

What diseases are associated with SOD1?

A

ALS

131
Q

What diseases are associated with Tau?

A

AD and CTE

132
Q

What diseases are associated with PrP?

A

BSE, CJD, Scrapie

133
Q

What diseases are associated with Amyloid Beta Peptide?

A

Alzheimers

134
Q

What diseases are associated with alpha-synuclien?

A

Parkinson’s Disease

135
Q

What diseases are associated with HD?

A

Huntington’s disease

136
Q

When alpha-helices misfold into a common cross-B helical core filament structure, what happens in the brain?

A

Leads to an aggregation of 8-10nm wide amyloid fibrils; Masses of amyloid fibrils form amyloid plaque in the brain; These disrupt cell function and cause neuronal apoptosis (brain cell death)

137
Q

Is misfolding caused by genetics or transmission?

A

Misfolding can be caused by genetics or transmission

138
Q

What does “Prion” stand for?

A

Proteinaceous Infectious Particle

139
Q

What “infection” do prions involve?

A

The “infection” involves a change of secondary structure and conformation in the pathogenic protein - converts from alpha-helical to beta-sheet conformation

140
Q

What is the good prion called? What about the bad prion?

A

Good = PrPc
Bad = PrPsc

141
Q

Is Prpc a proteasse resistant protein?

A

No (PrPsc is protease resistant)

142
Q

Who discovered prions?

A

Stanley Prusiner

143
Q

Can heat (autoclaving) be used to kill prions?

A

No

144
Q

Why was the discover of prions significant?

A

1st case of infectious agent being a protein

145
Q

What is p53 protein and why is it significant?

A

p53 is a tumor-suppressing protein; Initiates apoptosis in response to sever DNA damage (stops cancer before it grows)

146
Q

What do mutations in p53 lead to?

A

Mutations cause misfolding, which makes p53 incorrectly active; Thus, mutations in p53 can lead to unregulated cell growth (cancer)

147
Q

What is a super-secondary structure? (Motiff)

A

Small, commonly observed combinations of alpha-helices and beta-sheets

148
Q
A

Helix-Turn-Helix

149
Q
A

Coiled-Coil

150
Q
A

Zinc Finger

151
Q
A

Beta-Alpha-Beta unit

152
Q
A

Hairpin

153
Q
A

Beta-meander

154
Q
A

Greek Key

155
Q
A

Beta-Sandwhich

156
Q
A

Beta Barrel

157
Q
A

Alpha/Beta Barrel

158
Q

What is a Domain?

A

Independent folding regions within a protein often associated with a certain function or pattern of secondary structure

159
Q

What are domains connected by?

A

Domains are connected to each other by loops, bound by weak interactions between side chains

160
Q

Why are interfaces between domains significant?

A

Interfaces between domains provide crevices, grooves, and pockets that make good binding or catalytic sites; In multifunctional enzymes, each catalytic activity can be one of several domains.

161
Q

How are domains related to tertiary structure?

A

Domains are the fundamental unit of tertiary structure

162
Q

What are the 4 classes of protein structure?

A
163
Q

What are protein “folds”?

A

A “fold” is a combination of secondary structures that forms the core of a domain; Some domains have simple folds, which others have more complex folds; Folds can give elaborate motifs

164
Q

Describe this fold

A

EF-hand Fold (motif) - A helix-turn-helix fold that is often found in proteins that bind Ca2+ (ex. calmodulin)

165
Q

Describe this fold

A

Jelly/Swiss-barrel roll fold - “squished” form of antiparallel beta-barrel

166
Q

Describe this fold

A

TIM barrel fold (alpha/beta barrel)

167
Q

Describe this fold

A

Rossman Fold (aka dinucleotide binding fold)

168
Q

Describe this fold

A

Horseshoe Fold

169
Q

What is Quaternary Structure?

A

Organization of subunits in a protein with multiple subunits (multimer)

170
Q

What holds quaternary structure together?

A

Forces that hold the 4° structure together are the same as that of the 3° structure, EXCEPT for disulfide bonding (not found between subunits)

171
Q

Do proteins exhibit symmetry? Describe.

A

Multi-subunit proteins often display symmetry between subunits - rotational symmetry

172
Q

Does Myoglobin have quaternary structure?

A

No, it is a monomer

173
Q

Does Hemoglobin have quaternary structure?

A

Yes - It is a tetramer (has 4 homologous subunits)

174
Q

What was the first 3D protein structure determined? By who?

A

Myoglobin by John Kendrew

175
Q

How many alpha helices make up Myoglobin?

A

8 alpha-helices labeled A through H

176
Q

What is the difference between Mb and Hb?

A

Mb is a monomer; Hb is a tetramer

177
Q

What subunits make up Hb?

A

Hb is a tetramer of 4 Mb-like homologous subunits; Has 2 alpha-globin and 2 beta-globin subunits

178
Q

What structure is most similar in Mb and Hb?

A

Tertiary Structure; Primary structure is highly variant (they do not have the same AA sequence)

179
Q

Who solved Hb’s crystal structure?

A

Max Perutz

180
Q

What is the heme group?

A

Heme = Protoporphyrin IX + Fe(II)
Prosthetic Group

181
Q

What is a prosthetic group?

A

The non-AA portion of a protein that is required for biological activity

182
Q

What does heme allow proteins to do?

A

Bind Oxygen

183
Q

What is formed when oxygen binds to a heme group?

A

Octahedral Coordination complex

184
Q

What group coordinates oxygen binding in heme?

A

His F8

184
Q

When heme has oxygen on it, what color does it appear?

A

Red (oxygenated blood)

184
Q

What holds heme in place? (other than the coordinate covalent bond to His F8)

A

Hydrophobic Interactions
Val E11 and Phe CD1

184
Q

What is the difference between the proximal and distal Histidine? Why is the distal His important?

A

Proximal His is bound to the Heme group “by itself” on the bottom of the molecule
Distal His (His E7) forces any ligand binding to Fe(II) group in Heme to bind at a bent angle (this allows for O2 to bind Fe(II) reversibly

185
Q

What is another name for Distal His?

A

His E7

185
Q

How is His E7 important in preventing CO poisoning?

A

His E7 forces substrates to bind at a BENT ANGLE; CO has a very strong affinity for Fe(II) whenever it can bind linearly (20,000x stronger than O2)

186
Q

Describe the toxicity of CO without His E7

A

CO is still poisonous with His E7, but without His E7, it would be WAY MORE POISONOUS

187
Q

What is Methemoglobin and Metmyoglobin?

A

Some heme Fe(II) in Hb & Mb in presence of O2 gets oxidized to Fe(III) - Gives metHb and metMb

188
Q

Can metHb and metMb bind Oxygen?

A

No, they cannot

189
Q

What color is methemoglobin?

A

Bluish chocolate-brown

190
Q

What is the role of the enzyme diaphorase?

A

Reduces Fe(III) back to Fe(II) - Gives Hb & Mb ability to bind O2

191
Q

What is Heme dimerization?

A

2 hemes in solution (without protein) can get together and auto-oxidize through an intermediate where an O2 bridges between two Fe(II) centers

192
Q

What is the effect of heme dimerization?

A

Heme dimerization in Hb & Mb would give metHb/metMb where Fe(III) can no longer bind O2

193
Q

How is heme dimerization prevented?

A

Bulky groups around heme in hydrophobic cleft prevent oxidation of Fe(II), thus allowing reversible O2 binding

194
Q

What kind of binding curve does Mb have?

A

Hyperbolic O2 binding curve

195
Q

What is Mb’s p50?

A

2.8

196
Q

What kind of protein is Mb?

A

Oxygen Storage protein

197
Q

Does Mb give up a lot of oxygen under normal conditions?

A

No, it has a very high affinity for O2

198
Q

When does Mb release Oxygen?

A

Only in extremely low pO2 (high intensity exercise)

199
Q

How many oxygens can Hb bind?

A

4

200
Q

What is the primary role of Hb in the blood?

A

Hb transports O2 from lungs to tissues because diffusion alone is too poor for O2 transport in large animals

201
Q

What did researchers find whenever they exposed Hb to Urea? What are the subunits involved?

A

Urea breaks Hb into dimers labeled (a1-B1) and (a2-B2); Thus, Hb is a dimer of dimers

202
Q

Does Urea have an effect on the connections between (a1-B1) and (a2-B2) subunits?

A

No, the bonds between these subunits are too strong for Urea to break

203
Q

What accounts for the change in conformation between Hb and deoxyHb?

A

Quaternary structure (there is no structural change between Mb and deoxyMb)

204
Q

What is the name of the deoxy state of Hb?

A

T State (tense)

205
Q

What is the name of the oxy state of Hb?

A

R State (relaxed)

206
Q

What conformational change is involved in going from T-state to R-state?

A

Switch between states involves a 15° twist between aB dimer pairs

207
Q

What contacts are affected in the 15° rotation between T-state and R-state?

A

a1-B2 and a2-B1 contacts

208
Q

Describe affinities in the T-state and the R-state of Hb

A

T-state has a low O2 affinity & R-state has a high O2 affinity

209
Q

How does 1 O2 binding to Hb affect the T to R switch?

A

The first O2 that binds to the T-state “unlocks” the rest of the molecule, causing it to transition to the R state

210
Q

Why can communication between Hb subunits’ heme groups not be electronic?

A

The hemes are too far apart

211
Q

What kind of communication causes the switch from T-state to R-state?

A

Mechanical communication

212
Q

Who determined that Hb’s coopertivity came from mechanical movement of protein scaffold?

A

Perutz

213
Q

Describe the Perutz mechanism for Hb’s positive O2 binding coopertivity

A

1) T-state is locked in “tense” conformation by H-bonds and ion pairs that are not present in the R-state
2) Difficult for T-state to bind the 1st O2 - b/c His E7 and Val E11 block the 1st O2’s access to heme
3) In T-state, the Fe(II) iron is ~0.6A out of heme plane
4) When 1st O2 gets in and binds, it pulls Fe(II) back into heme plane
5) His F8 is attached to the Fe(II) is thus also pulled towards the heme plane
6) Because His F8 is part of F helix, it pulls the F helix down, causing F helix to move 1A
7) When F helix moves, aB pairs rotate 15° with respect to each other
8) T to R shift in quaternary structure causes His E7 and Val E11 to move out of the way, so that O2 has clear access to heme

214
Q

Why is it difficult for t-state to bind the 1st O2?

A

His E7 and Val E11 block heme from binding O2

215
Q

How does the 1st O2 eventually bind to the T-state/

A

Protein is dynamic and O2 concentration is increasing

216
Q

What happens to the conformation of the heme once the 1st O2 is able to bind?

A

Whenever the 1st O2 gets in and binds, it pulls Fe(II) back into the heme plane

217
Q

Which subunit does the first oxygen bind to?

A

No preference

218
Q

Why is it significant that a different but equivalent set of H-bonds and Ion pairs act like “knobs on a molecular switch”?

A

This essentially limits the conformations of Hb to only the T-state and the R-state (it has to be one or the other, due to the presence of the “molecular switch” bonds)

219
Q

What happens to His E7 and Val E11 when Hb moves into the R state?

A

His E7 (distal) and Val E11 move out of the way, allowing O2 to easily bind to the other subunits

220
Q

Where does the energy to break the ion pairs & H-bonds in the T-state come from?

A

The energy in the formation of the Fe-O2 bond formation drives the T-R transition

221
Q

What is the overall shape of the Hb curve?

A

Sigmoidal

222
Q

Describe how the positive coopertivity works for Hb

A

T-state has a low affinity for O2, while R-state has a high affinity for O2; The combination of these two states gives Hb a sigmoidal curve (indicating coopertivity)

223
Q

What is generally required for a coopertive effect?

A

Quaternary structure

224
Q

Does Mb have coopertivity?

A

No, because it does not have quaternary structure

225
Q

What does a hyperbola indicate about coopertivity? What about a sigmoidal curve?

A

Hyperbola = No Coopertivity
Sigmoidal = Coopertivity

226
Q

What is the p50 of Hb?

A

26 torr

227
Q

Does Mb or Hb have a higher affinity for O2?

A

Mb

228
Q

How was the Pertutz mechanism proven? Describe the experiment.

A

Replace His F8 with Gly, plus add imidazole to heme (this mimics structure of heme, without the covalent bond to His F8)
Whenever O2 binds to heme, it does not have the ability to cause conformational change in Hb, because F8 is not covalently bound to the heme prosthetic group

229
Q

Why is Hb the ideal O2 transport protein?

A

Hb is the “ideal” O2 transport protein because of its sigmoidal shaped binding curve
This gives Hb the ability to “load up” O2 in the lungs, and “dump it” in the capillaries

230
Q

What does p50 measure?

A

Affinity (low p50 = high affinity)

231
Q

What does Allostery mean?

A

“other site” - Binding at one site affects binding at others

232
Q

What is required for Allosterism to occur?

A

Allosterism requires proteins with at least 2 subunits

233
Q

What is an activator? Which was does it shift the curve?

A

Activator - Shifts the equilibrium towards the R-state (shifts curve UP)
= Positive allosteric interaction

234
Q

What is an inhibitor? Which was does it shift the curve?

A

Inhibitor - Shifts the equilibrium towards the T-state (shifts curve DOWN)
= Negative Allosteric interaction

235
Q

What is the difference between a homotropic and a heterotrophic activator/inhibitor?

A

Homotropic = Effector and ligand are the same molecule
Heterotropic = Effector and ligand are different molecules

236
Q

How is Hb’s oxygen affinity fine tuned?

A

The affinity of Hb for oxygen starts out high, but then is modulated by favoritng the T state in the equilibrium between T-state and R-state

237
Q

What are the 3 effects that shift Hb towards the T state? Is this homotropic or heterotropic? Activator or Inhibitor?

A

BPG, H+, and CO2 all shift Hb to the T-state (these are all heterotropic inhibitors

238
Q

Do activators/inhibitors have an effect on Mb?

A

No

239
Q

What is the Bohr effect?

A

Bohr discovered that increasing CO2, H+, Temp. all caused the release of O2 from Hb

240
Q

Which way does the curve shift in response to an increase in CO2, H+, and Temp. according to the Bohr effect?

A

Curve shifts right

241
Q

Which way does the curve shift whenever you remove Bohr inhibitors?

A

Left

242
Q

What is the role of Bohr Protons?

A

Bind and stabilize the T-state

243
Q

Where on the T-state do the Bohr Protons bind?

A

N-terminal amino groups (20-30% of Bohr effect)
His146B (40% of Bohr effect)

244
Q

How does the pKa’s of N-terminal amino gps and His146B affect the coordinated H+’s?

A

The T to R transition changes the pKa’s of these groups, causing them to release their coordinated H+

245
Q

Where on T-state does CO2 bind?

A

CO2 can react to form CARBAMATES with the N-terminal amino groups of blood proteins

246
Q

Is carbamate present in the R-state or the T-state?

A

Only the T-state

247
Q

Is Hb involved in CO2 transport?

A

Yes

248
Q

How does Carbonic Anhydrase contribute to the Bohr effect?

A

Carbonic Anhydrase makes CO2 soluble in blood, so that it can be absorbed by RBC’s and thus bound to Hb for transport to lungs (out of the body)

249
Q

How does CO2 concentration and pH change in lungs and tissues to contribute to the Bohr effect?

A

In the lungs, there is low amounts of CO2 and H+ (Favors R-state)
In the capillaries, there is high amounts of CO2 and H+ (Favors T-state)

250
Q

How does the curve shift in the capillaries vs. the lungs?

A

In the lungs, the curve shifts UP, while in the capillaries, the curve shifts DOWN

251
Q

What is the pH in Lungs? Capillaries?

A

pH in lungs = 7.6
pH in capillaries = 7.2

252
Q

Is BPG an allosteric inhibitor or activator? Is it heterotropic?

A

Allosteric inhibitor (heterotropic)

253
Q

Where does BPG bind in the T-state of Hb?

A

Central cavity is the perfect docking site for BPG

254
Q

How many BPG’s can be present in an Hb molecule?

A

1

255
Q

Can BPG bind to the R-state?

A

No, because there is not a central cavity (due to 15° shift)

256
Q

What is the concentration of BPG in normal blood?

A

5 mmol/L

257
Q

Why is BPG important for Hb? What is p50 of Hb without BPG? Why is this bad?

A

p50 without BPG = 12 torr
Affinity for O2 is TOO HIGH without BPG, so oxygen cannot be “dumped off” at tissues

258
Q

Does Cl- have allosteric effects on Myoglobin?

A

No

259
Q

What does Cl- do to Hb? Is it an activator or an inhibitor?

A

Cl- is a heterotropic inhibitor (shifts curve down)
Cl- binds to deoxy Hb (causes O2 release) (Chloride shift)

260
Q

How is Hb & Mb binding O2 similar to an enzyme binding its substrate?

A

Hb & Mb binding O2 occurs in the same way an enzyme binds its substrate

261
Q

What does the slope of the line in the Hill equation show?

A

Degree of coopertivity

262
Q

What do the different values of slope in the Hill equation indicate?

A

n=1 : Non-Cooperative
n>1 : Positive Coopertivity
n<1 : Negative Coopertivity

263
Q

Who developed the concerted model for allosteric proteins?

A

Monod, Wyman, and Changeux

264
Q

Describe the MWC Model for Allosteric Proteins

A

Subunits can exist in T or R conformational states, but all have to be in the same state
Equilibrium Between the T and R states
In the absence of Ligand, equilibrium favors T state
Ligand binding shifts equilibrium toward R state

265
Q

What is a limitation of the MWC model of coopertivity?

A

Only models positive cooperativity

266
Q

Who developed the induced fit model for allosteric proteins?

A

Koshland-Nemethy-Filmer (KNF “Knife” Model)

267
Q

Describe the Sequential (Induced Fit) Model for Allosteric Proteins

A

Presence of R-site induces increased affinity in adjacent sites; Thus, complete T to R transition is a sequential process

268
Q

Why is induced fit model better than MWC model for allosteric proteins?

A

Induced fit model accounts for both positive and negative cooperativity

269
Q

Does the Perutz mechanism work in coordination with the induced fit model?

A

Yes

270
Q

What is the difference between pathological and non-pathological substitution for protein mutations?

A

Pathological Substitution = Can affect structure & thus function; Can affect important active site residues
Non-pathological Substitution = Normally on surface of protein, don’t affect structure

271
Q

What do pathological mutations often lead to in Hb?

A

Many mutations in Hb stabilize MetHb, so that O2 binding is eliminated

272
Q

What is Cyanosis?

A

When Fe(III) form is stabilized, so blood cannot bind oxygen; Blood is a blue to chocolate brown color

273
Q

What is the Iwate Mutation in Hb?

A

“Black Mouth” (His F8 chagnes to Tyr)

274
Q

What is the “Hb Hammersmith” mutation? Why is this particularly significant?

A

Hb Hammersmith mutation is the change of Phe CD1 to Ser
This eliminates the ability of bulky groups to force substrates to bind at a BENT ANGLE, which is not good

275
Q

Are mutations on the surface of Hb typically dangerous?

A

No, not usually

276
Q

What is one example of a surface mutation on Hb? What is the mutation change?

A

Hb(S) - Sickle Cell Anemia
(Glu 6 on Beta Chains changes to Val)

277
Q

What kind of inheritance does sickle-cell anemia exhibit?

A

Autosomal Recessive

278
Q

Does normal Hb and Sickle-Cell Hb have the same oxygen-binding ability?

A

Yes

279
Q

Describe the Pathology of Hb(S)

A
  • Long linear polymers (fibers) form in RBC due to Val substitution in Beta Chain
  • In Capillaries, Hbs lose O2, causing change to T-state
  • In T-state, polymerization causes blood cells to sickle
  • Sickled RBC’s block blood flow (pain crisis)
280
Q

Can Heterozygous subjects experience pain crisis with sickle-cell anemia?

A

Yes, but only under extreme physical activity when lots of oxygen is needed in the body

281
Q

What is the benefit of the Hb(S) gene?

A

Hb(S) confers protection from malaria for heterozygous individuals

282
Q

Who discovered that sickle-cell anemia is caused by an alteration in Hb’s molecular structure?

A

Linus Pauling

283
Q

What is significant in Gamma Hb?

A

Gamme Hb is “Fetal Hb”

284
Q

How is O2 transferred from mother to fetus? What molecule is important for this?

A

In the presence of BPG, Hb(F) has a higher affinity for O2 than Hb; This allows transfer of O2 from the mother to the baby
Hb(F) is LESS INHIBITED BY BPG

CHE 4341 Baylor (Dr. Jonklaas) (14 decks)

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