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Biochemistry & Molecular Biology > L3-5: Structure of Protein I, II & III > Flashcards

L3-5: Structure of Protein I, II & III Flashcards

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1
Q

What is the structure of histidine? What are the properties of this AA? What is it’s pKa?

A

-histidine, basic, pKa = 6.00

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2
Q

Describe what happens at a molecular level when oxygen binds to a heme in deoxygenated hemoglobin. How do these events contribute to allosterism? How does the oxygen-binding behavior of hemoglobin translate into an efficient oxygen carrier?

A

Deoxygenated Hb is in a T-form (tight) with low o2 affinity. A valine reside partially blocks the o2 binding site in the beta subunits. When o2 concentration increases (ie. in lungs), o2 is forced by mere concentration onto alpha subunits. A conformational change occurs as a result of this binding and the valine residues are rotated out of the o2 binding site in the beta subunits. The Hb molecule is now in a high o2 affinity form known as the R-form (relaxed). The importance of this is considered when looking at the physiological range when o2 is loaded / unloaded from Hb.

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3
Q

What are the properties of this AA?

A

-cysteine, polar uncharged

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4
Q

What are the properties of this AA?

A

-glutamine, polar uncharged

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5
Q

What is collagen?

A

Collagens are the most abundant family of proteins in the body. They are glycoproteins of CT. It is composed of triple helical units, ie. three polypeptide chains wrapped around each other. These are not alpha-helices as the helix turns to left and also, proline is present. The helices are held together covalently.

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6
Q

What are the properties of this AA?

A

-asparagine, polar uncharged

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7
Q

How do the oxygen-binding properties of HbF and HbA1 differ? Why is this important?

A
  • HbA1 refers to the alpha2beta2 Hb tetramer, which is the most common form in adults, account for over 90% of total in blood - HbF is the predominant Hb tetramer present in the 2nd/3rd trimester of development. In contrast to adult Hb, HbF curve is shifted to the left indicating that at a specific o2 pressure, HbF is more saturated than adult Hb. Has higher affinity for o2 than adult Hb. This ensures that the fetus’ high metabolic o2 requirements are met. - This is due to the replacement of a histidine residue with a serine residue in the gamma chain of HbF. As a result, HbF has reduced affinity for 2,3-BPG and is left shifted.
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8
Q

Describe the 4 main groups of amino acids. What are their characteristics?

A

a.) non-polar, aliphatic: hydrophobic and chained/branched, found interior aspect of proteins, uncharged Gly, Ala, Val, Leu, Ile, Met, Pro • Gly – no asymmetric carbon (2 Hs) • Pro – ring structure • Met – sulfur-containing AA b.) aromatic: hydrophobic (non-polar rings), often found interior of water-soluble proteins, uncharged Phe, Tyr, Trp • Tyr – has OH group and can be phosphorylated c.) polar, uncharged: hydrogen bond, interior/exterior of proteins Ser, Thr, Cys, Asn, Gln • Ser/Thr – have OH groups that can be phosphorylated • Cys – sulfur-containing AA, forms disulfide bridges with other thiol containing molecules (ie. cystine = 2 cysteines) d.) Ionizable side chained AA – basic/acidic: Acidic: Asp, Glu (net -1 charge at physiological pH) Basic: Lys, Arg, His* (net +1 charge at physiological pH) * His can be basic/uncharged as pKa = 6.0

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9
Q

What is meant by the term “post-translational modification”?

A

Post-translational modifications refer to changes made to protein following translation from RNA to protein. This includes attachment of prosthetic groups, glycosylation, lipid attachments, phosphorylation and proteolysis.

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10
Q

Describe the tertiary structure of myoglobin. What is the essential prosthetic group in myoglobin and what is its function?

A

Myoglobin is an oxygen binding protein found in muscle tissue. It comprises eight alpha-helices. Mb has a heme prosthetic group, which is a porphyrin ring bound to iron. Binding of oxygen occurs at iron. It effectively binds oxygen at low concentrations.

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11
Q

Describe the structural features of an α-helix. What amino acid is disruptive to the formation of α-helices?

A

Alpha helices are rod shaped spirals where the polypeptide chain winds in a clockwise direction. Each peptidyl C=O is hydrogen bonded to H-N groups four amino acids down the chain. Proline residues disrupt the H-bonding of the alpha helix by putting a sharp bend in the polypeptide. Bulky R-groups of multiple like-charged R-groups can block the formation of alpha helices.

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12
Q

What is meant by the term “hemoglobinopathy”?

A

This refers to pathologies related to Hb structure.

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13
Q

The formation of native protein structure is said to be cooperative. What does this mean? Outline the ‘seeding and nucleation’ model for the progression of prion diseases, Parkinson disease, and Alzheimer disease. What proteins are associated with these disease states?

A

Cooperative native protein structure indicates that the protein folding cannot be a random process, but instead occurs through favored pathways. This involves the rapid formation of short stable segments of secondary structure, which generate structural motifs which continue to fold into a thermodynamically stable protein structure. The seeding/nucleation model is where a misshaped protein (typically beta-sheets) induces other proteins (during folding) to change confirmation, which has a trickle down/domino effect on other proteins. Parkinson’s: alpha-synuclein is implicated, affect NT release (?) Alzheimer’s: tau and amyloid-beta are implicated, affecting microtubule (?) and neuronal plasticity (?) respectively

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14
Q

Describe how a mutation in the amino acid sequence could affect protein structure and/or function. Give several examples.

A

A change in amino acid sequence will lead to different interactions and therefore different folding (see 14). Different structure will confer different function. The original purpose of the protein can no longer be served. Examples of diseases where misfolded proteins are implicated: • CJD: inherited or spontaneous • Kuru: infectious • vCJD: infectious Above diseases lead to spongiform encephalopathies (neurodegeneration, brain becomes spongy) • Parkinson’s: loss of dopaminergic neurons, formation of Lewy bodies (aggregates of alpha-synuclei protein seeds more) leads to tremor, bradykinesia, postural instability • Alzheimer’s: neurological condition leading to dementia from plaque/fibrillary structures in brain containing amyloid-beta and tau proteins that seeds more

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15
Q

Explain what occurs to the Hb binding curve as pH, 2,3-BPG, temp, CO2 change? Draw it.

A
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16
Q

Identify the α-carbon and an L-amino acid. Which amino acid does not have a chiral α-carbon?

A

The alpha-carbon is the central carbon to each amino acid. All amino acids except glycine have a chiral alpha-carbon and will have either a D or L stereoisomer. All mammalian proteins contain only L-amino acids.

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17
Q

What are the properties of this AA?

A

-phenylalanine, aromatic hydrophobic

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18
Q

What are the properties of this AA?

A

-tryptophan, aromatic hydrophobic mostly, slightly polar

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19
Q

What are the properties of this AA?

A

-tyrosine, aromatic hydrophobic (typically)

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20
Q

Define primary structure, secondary structure, tertiary structure, and quaternary protein structure.

A

a. Primary structure: the amino acid sequence of the polypeptide chain b. Secondary structure: a segment of polypeptide chain that has regular repeating structure. Results from H-bonding between the C=O and H-N groups of the polypeptide backbone. Alpha-helices and beta-pleated sheets. c. Tertiary structure: the 3D structure resulting from the interaction of various secondary structures and non-ordered regions of the polypeptide chain, results from disulfide bridges (covalent) and hydrogen bonding, ionic interactions (salt bridges) an hydrophobic forces (all non-covalent) d. Quaternary structure: protein molecules that have more than one subunit, each with tertiary structure, have overall quaternary structure. The subunits associate through same forces found in tertiary structures

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21
Q

What are the properties of this AA?

A

-Glycine, non-polar

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22
Q

Identify the amino acids that contain sulfur.

A

Met, Cys

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23
Q

What are the properties of this AA?

A

-threonine, polar uncharged

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24
Q

Describe the quaternary structure of hemoglobin. Compare and contrast the structure and oxygen binding properties of hemoglobin and myoglobin.

A

Hemoglobin is comprised of two alpha-globulin subunits and two beta-globulin subunits. Each has an iron containing heme prosthetic group. The hemoglobin forms by association of two alpha-beta-dimers which interact through H-bonds and salt bridges. Each subunit resembles that of myoglobin. Myoglobin has high affinity for o2 at low partial pressures of oxygen (hyperbolic o2 binding curve), whereas hemoglobin has a lower affinity for oxygen at lower partial pressures and its affinity increases as partial pressures increase and a conformational change takes place (sigmoid binding curve), changing affinity of each heme group that is to be “loaded.”

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25
Q

Explain how 2,3-BPG; CO2 and H+ influence Hb’s affinity for oxygen. Provide physiological relevance.

A
  • Increase in 2,3-BPG decreases Hb’s affinity for o2 (binds in central cavity, stabilizing T-form through strong ionic interactions) promoting release - Increase in H+ conc (low pH) decreases Hb’s affinity as they bind His, forming positive residue which binds aspartate, stabilizing T-form and promoting o2 release - CO2 binds to N-terminal of Hb subunits forming carbamates. Carbamates carry a negative charge and participate in salt bridges that stabilize T-form, promoting o2 release Physiological relevance: In rapidly metabolizing tissue, CO2 and proton concentration is high, o2 requirement is high. Protonated His and carbamate formation stabilize the T-form of Hb resulting in offloading of o2 here. Conversely, in lungs, removal of CO2 (requiring proton with bicarb ion), causes deprotonation of Hb and conversion to R-form where conveniently o2 tension is also high. Amount of o2 carried to peripheral tissues increases as a result.
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26
Q

What are the properties of this AA?

A

-proline, non-polar

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27
Q

What are the properties of this AA?

A

-glutamate, acidic

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28
Q

What is meant by a prosthetic group?

A

Many proteins require association of metal ions and / or certain organic molecules in order for them to function. Prosthetic groups are associated organic molecules permanently bound to them.

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29
Q

What are the properties of this AA?

A

-leucine, non-polar

30
Q

Explain the charges of the carboxy and amino terminals of an amino acid at pH 1, 7 and 14

A

pH 1: both groups are protonated, therefore +1 charge pH 7: amino group is protonated, carboxy is deprotonated, therefore neutral pH 14: both groups are deprotonated, therefore -1 charge

31
Q

Which amino acids are more likely to be found on the surface of a water-soluble globular protein? The interior?

A

1.) non-polar, aliphatic; 2.) aromatic; 3.) polar, uncharged = found interior 3.) polar, uncharged; 4.) ionizable, ie. acidic / basic = found exterior

32
Q

What are protein domains?

A

Large polypeptides fold in discrete lobes known as domains. These are areas are independently folded into a stable structure. Think bead on string of beads.

33
Q

What are the properties of this AA?

A

-serine, polar uncharged

34
Q

What are the factors that influence Hb’s affinity for oxygen

A

2,3-BPG (aka DPG); CO2, pH (protons), temperature

35
Q

What are the properties of this AA?

A

-aspartate, acidic

36
Q

What are other pathologies related to mutations in collagen?

A
  • Ehlers-Danlos: CT disorder characterized by skin fragility, skin hyperextensibility and joint hypermobility resulting from mutations in collage proteins or proteins required for collage processed. Some benign symptoms, others complicated including bowel and arterial rupture. - Osteogenesis imperfecta: brittle bone diseases characterized by fragile bones, abnormalities in teeth, hearing losss. It can be lethal, otherwise individuals can have normal lifespan with slightly reduced bone mass.
37
Q

Explain the biochemistry of CO (carbon monoxide poisoning).

A
  • CO binds to heme iron at ~ 240 higher affinity than o2 (known as carboxyhemoglobin) - When 2 x CO molecules bind to Hb, R-form stabilizing, meaning T-form unfavored and o2 wants to remain bound and not deliver to tissue. - Treatment is removing individual from CO and administering 100% o2 at high pressure.
38
Q

Regarding the molecular structure of collagen, describe: a. the importance of amino acid composition and sequence. b. unusual amino acids and their molecular function. c. the importance of vitamin-C and iron in collagen formation.

A

a. the importance of amino acid composition and sequence. - Collage contains 35% glycine, 11% alanine and modified amino acids known as 4-hydroxyproline and 5-hydroxylysine (previously proline and lysine, but post-translationally modified). - Collage contains the repeating sequence Gly-Pro-Hydroxyproline. Since three polypeptides (in helices) are to come together, it would be important for a smaller residue to be present at the contact points. This is the case, glycine is found here, which has R group of H. b. unusual amino acids and their molecular function. - Collagen has two unusual/modified amino acids known as 4-hydroxyproline and 5-hydroxylysine. Without proline-peptide and peptide-hydroxyproline bonds, helix and triple helix formation would not be possible. Also, strength and rigidity of the molecule would also be compromised. Therefore functional would be lost. Stability is also present in collage as a result of hydrogen bonds formed by hydroxyproline. Lastly, hydroxylysine allows for covalent linkages between helices to form via reactive aldehyde functional groups. c. the importance of vitamin-C and iron in collagen formation. - Ascorbate (vit C) is necessary to catalyze the reaction of proline to hydroxyproline via the prolyl hydroxylase enzyme. This occurs in conjunction with Fe2+ and alpha-ketoglutarate. Ascorbate is required to reduce Fe3+ to Fe2+ in the reaction and allow the enzyme to remain active. Without vit C, enzyme is inactivated and scurvy develops. - Remember hydroxylation in collage allows for normal collagen fibril formation. Without, you have collagen that lacks strength, rigidity and stability.

39
Q

What are the properties of this AA?

A

-lysine, basic

40
Q

Describe the properties of HbS, the variant of hemoglobin found in sickle cell anemia.

A
  • HbS is an altered Hb structure where a glutamate residue in the beta chain has been substituted for valine. Glu is a acidic hydrophilic AA, which valine is a non-polar, aliphatic AA. As a result, a “sticky hydrophobic pathy” is generated in the betal chains. When in the R-form, it is shielded from water. When in the T-form; however, it is exposed to surface. When in this form, it interacts with other Hb molecules to avoid interaction in polar environment and polymerization of poly Hb is catalyzed. This distores the shape of RBCs. Cells block blood vessels and damage organs.
41
Q

Draw the structure of the tripeptide in which lysine is the N-terminal amino acid, glutamate is the second amino acid, and phenylalanine is the C-terminal amino acid. What is the sequence of this tripeptide using the three letter abbreviations. Considering this tripeptide, what would be the net charge at pH 1.0, pH 7.0, and pH 14?

A

Lys-Glu-Phe

pH1: protonated terminals, net charge +2

pH7: protonated amino, deprotonated carboxy = neutral molecule, net charge 0

pH14: deprotonated terminals, net charge -2

42
Q

How is the structure of proline different from that of other amino acids?

A

Proline’s structure is different from the other amino acids because it forms a secondary alpha-amine through binding of the R-group to the alpha-amine forming a ring.

43
Q

Describe the structure of a reverse turn.

A

Reverse turns allows polypeptides to change direction and loop back on itself. They are stabilized by hydrogen bonding between the C=O of the first amino acid and the H-N of the fourth amino acid of the loop. They are frequently found in antiparallel B-pleated sheet. Proline and Glycine are often found in reverse turns.

44
Q

Describe how the amino acid sequence determines the structure and function of a protein.

A

The amino acid sequence of a protein determines how it folds into secondary, and then tertiary structures. Each amino acid has definitive properties, ie. non-polar, polar, hydrophobic, hydrophilic, charge, uncharged etc. Interactions between these amino acids via repulsion or attraction, furthermore via non-covalent and covalent bonding determines 2nd, 3rd and 4th order structure. Hydrophobic groups tend to move interiorly away from water and hydrophilic and charged are exposed exteriorly. The folding occurs through favored pathways in a cooperative manner until the protein is thermodynamically stable. STRUCTURE = FUNCTION!

45
Q

Describe the structure of the peptide bond. Which bonds in the peptide structure are free to rotate and which are restricted?

A

Peptide bonds are linkages between amino acids to form polypeptide chains. It is formed by a dehydration reaction between the alpha carboxyl group of one amino acid and the alpha amino group of another. It is a hybrid of two resonance states that impart partial double bond character to the bond which prevents free rotation around the peptide bond and makes it flat and planar

46
Q

What is meant by an apoprotein?

A

An apoprotein is a protein that is lacking its prosthetic group and has only native structure.

47
Q

What are the properties of this AA?

A

-arginine, basic

48
Q

What are the properties of this AA?

A

-methionine, non-polar

49
Q

What are the properties of this AA?

A

-isoleucine, non-polar

50
Q

List the various bonding interactions that stabilize a native protein structure.

A

a. hydrogen bonds: occur between peptidyl C=O and N-H groups as well as polar R-groups of some amino acids b. salt bridge: or ionic interactions occur between positively and negatively charged pairs of amino acids c. hydrophobic forces: represent interactions between hydrophobic amino acids d. van der waals attractions: weak attractive forces between atoms in close proximity to each other. • above are non-covalent • Covalent bonds are the disulfide bridges that occur in secondary and quaternary structures via cysteines

51
Q

What are the properties of this AA?

A

-Alanine, non-polar

52
Q

Describe the structural features of β-pleated sheets.

A

Beta pleated sheets are formed when 2 or more polypeptide chains or segments of chain line up next to each other and are held together by interchain H-bonds of the backbond C=O and N-H groups. The R-groups project above and below the plane of the sheet structure. They can be parallel or anti-parallel.

53
Q

What is protein denaturation and what are several factors that can denature a protein?

A

Protein denaturation occurs when the native structure of a protein is disrupted. This can occur due to a variety of factors such as increased temperature, detergents, pH extremes or certain chemical agents. Non-covalent forces are disrupted, but not covalent.

54
Q

What are the properties of this AA?

A

-Valine, non-polar

55
Q

Explain the difference between the T and R form of Hb.

A
  • T-form refers to the tight form of Hb and occurs when Hb is deoxygenated. In this form, Hb does not have high affinity for o2. At the tissue level where low pH, high CO2 and high 2,3-BPG are present, the tight form is favored and o2 is offloaded. - R-form refers to relaxed form of Hb when it has a high affinity for o2 molecules. This occurs in alveoli where high pH, low CO2 and low 2,3-BPG are present.
56
Q

What is the Bohr effect? What causes it to occur?

A
  • It refers to oxygen’s binding affinity of Hb being inversely related to acidity and concentration of CO2.
  • When CO2 concentration is high and acidic environment exists, o2 affinity for Hb is low and therefore Hb is more likely to give up o2 in tissues where this environment exists.
  • Causes: H+ binds to histidines foming stabilized T-form salt bridge; CO2 binds to N-terminus forming negatively charged carbamates increasing stabilization of T-form.
57
Q

What is the Bohr effect? What causes it to occur?

A
  • It refers to oxygen’s binding affinity of Hb being inversely related to acidity and concentration of CO2.
  • When CO2 concentration is high and acidic environment exists, o2 affinity for Hb is low and therefore Hb is more likely to give up o2 in tissues where this environment exists.
  • Causes: H+ binds to histidines foming stabilized T-form salt bridge; CO2 binds to N-terminus forming negatively charged carbamates increasing stabilization of T-form.
58
Q

Which amino acid residue is different in fetal Hb?

A

-Histidine residue in beta chain (adult) is replaced by serine in gamma chain (fetal). This is where 2,3-BPG usually binds in adults. Reduced affinity in HbF.

59
Q

What is methemoglobin?

A

-Type of hemoglobinopathy. This is Hb where Fe2+ is oxidized to Fe3+ and has reduced ability to deliver o2 to tissues.

60
Q

Which amino acids in collagen are responsible for covalent bonds in mature collagen? Where do these bonds exist?

A

-hydroxylysine/lysine form covalent bonds (aldehydic reaction) between helices in mature collagen

61
Q

What amino acids account for the strength and rigidity in collagen?

A

-peptide-proline and peptide-hydroxyproline

62
Q

What does the formation of hydroxyproline and hydroxylysine require?

A

-Fe2+, ascorbate and alpha-ketoglutarate in addition to enzyme.

63
Q

What is scurvy?

A

-Scurvy is the result of vit C deficiency. Blood vessels, tendons and skin become fragile. Symptoms include malaise, lethargy, easy bruising, dry skin, loosening of teeth, sleep disturbances and leg pain.

64
Q

What amino acid change occurs resulting in: (Explain each)

a. )HbS
b. )HbF
c. )Hbsaki/Hbgenova

A
  • a.) Glu to Val. Valine residue is sticky when in T-form, polymerizes with other sticky residues.
  • b.) His to Ser. Serine has decreased affinity for 2,3-BPG.
  • c.) Val to Pro. Proline breaks alpha-helix resulting in unstable Hb molecule, unable to bind o2 (or decreased affinity?)
65
Q

What changes occur that result in metHb?

A

-Fe3+ is the predominant form and there are no enzymes to oxidize back to Fe2+

66
Q

To what AA residue does 2,3-BPG bind on Hb? Result.

A

-His. Causes stabilization of T-form.

67
Q

What does CO2 bind to on Hb?

A

-N-terminus. Causes formation of carbamate, forms salt bridge which stabilizes T-form.

68
Q

What do protons bind to on Hb?

A

-His. Causes formation of salt bridge, which stabilizes T-form.

69
Q

What residues cover the o2 binding site in the beta subunits of Hb prior to existing in R-form?

A

-Valine. When rotated out, R-form is stabilized.

70
Q

What AAs are found in reverse turns?

A

-Pro and/or Gly with H-bond between 1st and 4th AA of turn.

71
Q

What secondary structure predominates in the disease scrapie?

A

-Beta-sheet

Biochemistry & Molecular Biology (47 decks)

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