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PHARM 310 > Antibody Structure & B-Cell Diversity > Flashcards

Antibody Structure & B-Cell Diversity Flashcards

1
Q

What is the D region

A

The Diversity region, the second region on the heavy chain locus (Green Box)
- Only found on the heavy chain

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2
Q

Protein Coding Process

A
  1. RNA Transcription (Here is where introns are removed) creating mRNA
  2. In the ribosome mRNA is translated into a polypeptide chain
  3. Once this chain exceeds 40-50 amino acids it is then considered a protein
  4. After translation Polypeptide Glycosylation occurs in the Golgi and ER
  5. After translation Polypeptides are sorted and targeted by cells occurs in the ER

Summary:
RNA –> mRNA –> Protein

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3
Q

What kind of bond links the polypeptide chains

A

Disulfide bond

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4
Q

How does the Antibody’s structure effect its function

A

Determines how many domains the heavy chain has
(3 Domains = IgG, IgA, IgD,)
(4 Domains = IgM, IgE)

Antigen Binding Loops at the end are formed by helix to sheet transitions.
These fingerlike projections (Paratopes, antigen binding sites) are solvent accessible spaces allowing molecules to move through the finger loops and interact with the protein structure

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5
Q

Polypeptide vs Protein

A

1 Amino acid = Amino acid

2 or more Amino acid = Polypeptide

Polypeptides that are greater than 40-50 amino acids = Proteins

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6
Q

IgA Isotype
- Attributes
- Functions
- Properties

A

Attributes:
- Secreted as a dimer using the J chain

Functions:
- Neutralization

Properties
- Can penetrate through epithelial barriers

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7
Q

What links the chains on an antibody

A

Disulfide bonds

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8
Q

What determines the shape of an antibody

A

Heavy chains wobble in ER and fold upon themselves to form a tertiary structure (Through hydrophilic, hydrophobic, hydrogen bonds)
- Primary Structure: Amino acid structure
- Secondary Structure: Alpha helices, beta pleated sheets
- Tertiary Structure: Final antibody structure

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9
Q

Half life of different Ig Isotypes

A

IgG have the longest

IgM have the second longest

IgA have the third longest

IgE have the shortest

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10
Q

What Sections are joined together in Gene Recombination of Heavy Chains

A

Diversity Domain is joined with the Joined Domain
- This DJ Domain is joined with the Variable Domain
- Variable Domain is made up of three hypervariable regions
- The third hypervariable region is coded by a splice from both the Variable Domain and the Joined Domain

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11
Q

What contributes to the immense amount of diversity in Ig genes

A

Somatic Recombination
- V, D, J, C Domains

Somatic Hypermutation
- Rapidly dividing daughter cells that introduce random polymorphisms

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12
Q

What is a Paratope

A

Antigen Binding Site located on the Antibody
- Made up of Hypervariable Regions / Complementary Determining Regions

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13
Q

How do the variable and constant regions differ on the varying isotypes

A

Variable:
- Only differ by specificity, specific isotype does not impact variable region

Constant
- Different C-regions give rise to different effector functions

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14
Q

What chains of Ig are first to be transcribed, from what Isotype?

A

IgM and IgD Constant regions are the first to be transcribed

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15
Q

What is the J Region

A

The Joining region, the second region on the light chain locus, and the third region on the heavy chain locus (Yellow Box)

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16
Q

What directs the RAG Enzyme Recombination Process

A

Recombination Signal Sequences (RSS)
- Two Types
1. Heptamer
2. Nonamer

Separated by 12 and 23 base pair spacers (12/23 Rule)
- Provides the right amount of space for the RAG enzyme to insert itself

RAG always cuts at the Heptamer

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17
Q

IgG Isotype
- Attributes
- Functions
- Properties

A

Attributes
- Long half life

Functions:
- Great at everything
- Neutralization
- Opsonization
- Activating complement system
- Sensitizing cells for killing by NK cells

Properties:
- Transport across placenta
- Transport across extravascular spaces

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18
Q

What creates diversity in antibody proteins

A

Lymphocytes rearrange the DNA before RNA transcription

NOT from the variations in enzymes splicing of introns

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19
Q

What is the C region

A

The Constant region, the third region on the light chain locus, and the forth region on the heavy chain locus (Blue Box)
- Codes for the domains of folded amino acids structures in the antibody’s constant region

Domains are linked together like a traditional gene, no DNA recombination, are ready to be transcribed
- Enzymes still have to splice off the introns

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20
Q

What Isotype is secreted first

A

IgM is secreted first as a pentamer

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21
Q

What are the different Antibody Isotypes

A

Heavy Chain:
IgG (Gamma), IgA (Alpha), IgM (Mu), IgE (Epsilon), IgD (Delta)

Light Chain:
Kappa and Lambda

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22
Q

How many chains on an antibody

A

4 polypeptide chains
- 2 heavy chains (On the inside and make up the main body too)
- 2 light chains (On the outside)

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23
Q

What are the seven changes that a Ig gene will experience

A
  1. Assembly of the V-region
    - Through Somatic Recombination
  2. Generation of Junctional Diversity
    - Due to imperfect rearrangement nucleotides are inserted and removed
  3. Assembly of Transcriptional Elements
  4. Transcription is activated, IgM and IgD are expressed through differential splicing
    - Reversible
  5. Membrane Ig or Secreted Antibody are produced depending on the presence of a Hydrophobic MC Region
    - Reversible
  6. Somatic Hypermutation
  7. Isotype Switching
    - Recombination involving downstream constant domain
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24
Q

What codes proteins

A

Segments DNA (genes) code for proteins
- Specifically Exons are the coding segments
- While Introns are the non-coding (intervening) segments

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25
Q

IgM Isotype
- Attributes
- Functions
- Properties

A

Attributes:
- Very large pentamer
- Relatively fast half life for quick immune response

Function:
- Activates Complement System

Property:
- Can transport across epithelium but have to squeeze through due to their large size

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26
Q

Gene Segment Recombination for Light Chain vs Heavy Chain

A

Light Chain
- V is joined to J

Heavy Chain
- D is joined to J
- DJ is joined to V

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27
Q

Differences in the different Antibody Isotypes

A

IgM and IgE have 4 domains compared the standard 3 domains

Each isotype have differences in glycosylation
- Extra bumps for antigenicity
- Affects their function

28
Q

Immunoglobulin vs Antibody

A

Antibodies are the excreted form of Immunoglobulins

Immunoglobulins of one specificity are expressed on the surface of B cells

29
Q

How are surface Ig expressed

A
  1. Separate Ig molecules enter the ER and self-assemble into Ig molecules
  2. These Ig molecules also contain a Hydrophobic Membrane Coding Region
  3. The newly created immunoglobulin is then tethered to the cell membrane and expressed as a B receptor
  4. Ig associates with disulfide-linked transmembrane proteins (Ig-alpha and Ig-beta)
  5. Signals to the B-cell that the surface Ig has bound an antigen
30
Q

What is a Hypervariable Region

A

Variable region
- Lots of variability in the amino acids found here
- Provides complementary to the shape, charge, hydrogen, hydrophobicity, polarity, hydrophilicity

31
Q

What Sections are joined together in Gene Recombination of Light Chains

A

Variable Domain is Joined with the Joined Domain
- Variable Domain is made up of three hypervariable regions
- The third hypervariable region is coded by a splice from both the Variable Domain and the Joined Domain

32
Q

What is the process of Recombination Switching

A
  1. IgM and IgD are co-expressed depending on mRNA splicing of the primary RNA transcript
  2. Further looping of the constant region leads to the switching to a different isotype
  3. Either IgA, IgE, IgG is produced
33
Q

What is an Epitope

A

Antibody Binding Site located on the Antigen
- Usually carbohydrates, proteins, or both
- Usually are macromolecules (Protein, Carbohydrates, Lipids)
- Usually multivalent

34
Q

What is the V Region

A

Variable Region, the first region (Red Boxes) on the locus
- Contains many different exons that can be chosen to determine the specificity

Lamda Light: 30 Variabilities
Kappa Light: 40 Variabilities
Heavy: 65 Variabilities

35
Q

What is a Complementarity Determining Regions

A

Provide a binding surface complementary to the antigen

36
Q

Define Germline Configuration

A

The genome found in every cells, in Ig cells the Germline Configuration is comprised of many Ig gene loci

37
Q

What is a Framework Region

A

Non-variable region,
- Is hydrophobic so it pushes away from the solvent accessible space
- Binds by disulfide bonding

38
Q

Variable Region Domain

A

Single Variable Domain
- With one on the light chain (VH) and one on the heavy chain (VL)

39
Q

Which Ig isotypes are transcribed first
- How are the other Isotypes transcribed

A

Depending on how the exons and introns are cut and splice either IgM or IgD are transcribed and are co-expressed
- The rest are transcribed by looping of the constant region

40
Q

IgE Isotype
- Attributes
- Functions
- Properties

A

Attributes
- Bit larger due to having an extra domain

Functions:
- Immediately taken up by mast cells
- Allergic response

Properties

41
Q

What is a Domain on an antibody

A

Immunoglobulin domains are made up of subunits of 100-110 amino acids joined together as a polypeptide

42
Q

What is Aby Affinity Maturation

A

Antibody becomes more specific for the antigen that is triggering it
- Caused by Somatic Hypermutation choosing a more specific Ig for the specific antibody

43
Q

Constant Region Domain

A

Single Non-Variable Domain
- Little to no amino acid diversity

44
Q

What is polypeptide sorting and targeting by cells?

A

Based on transcription each protein will have a different function
- They can be secreted
- They can be inserted into the phospholipid bilayer and expressed on the cell membrane

45
Q

What non-covalent bindings contribute to antigen-antibody binding

A

Ionic Bonds
Hydrogen Bonds
Van der Waals Attractions
Hydrophobic Attraction

46
Q

What do lymphocytes have that allow for Gene Segment Reccombination

A

Recombination Activating Genes (RAG)
- RAG-1 and RAG-2 are found only in Lymphocytes (B-Cells and T-Cells)

Other enzymes found in all nucleated cells are also used to repair DNA breaks

47
Q

What is Allelic Exclusion

A

Lymphocyte has chosen to stick with one variable region. No further variable rearrangement can occur
- Lymphocyte will only produce one type of Ig

However, Ig can rearrange further downstream heavy chains to choose a future different isotype

48
Q

Why is Glycosylation important in the immune response?

A

Changes the antigenicity when protein is glycosylated

Important because Mammalian Polypeptides are glycosylated.
- While bacteria (prokaryotes) can not glycosylate

49
Q

What is an Antibody Isotype?

A

Different classes of antibody’s
- Genetic Variations in the constant regions of the heavy chain and light chain

50
Q

In the seven steps of a Ig Gene which steps are reversible

A

Co-expression of IgM and IgD

Synthesis changes from membrane Ig to secreted antibody

51
Q

IgD Isotype
- Attributes
- Functions
- Properties

A

Attributes:
- Nothing too notable

Functions:
- Instructor of self and non-self

Properties:
- Nothing too notable

52
Q

Aby Functional Regions
- How it was found?
- Names of fragments
- Function of fragments

A

Plant Protease Papain cleaves antibody into 3 fragments

Gut Protease Pepsin degrades Fc, antibody can now no longer tag molecules

2 Fab (Important for antigen binding)
1 Fc (Important for opsonization, tagging molecules for disposable)

53
Q

Is Immunoglobulin diversity generated before or after encounter with an antigen

A

Occurs before

54
Q

How are Ig genes different from other genes

A

Except in B-Cells Ig genes are fragmented
- The B-cell can then rearrange the fragments to create a gene segment that is then transcribed and translated

55
Q

How do antibodies bind antigens

A

Molecular Complementarity
- Shape, Charge, Polarity, Hydrophobicity
Non-Covalent Binding

56
Q

Define Gene segment

A

Ig genes are fragmented, each fragment section is a gene section or a Ig gene locus

57
Q

Surface Ig Form vs Secreted Ig Form

A

Derived by the same process of enzyme recombination
- Just the Surface Ig contain a Hydrophobic Membrane Coding Region

58
Q

What Loci make up the Germline of an Ig Gene

A
  • 1 Set of Fragmented Genes that code for Lamda light-chain locus
  • 1 Set of Fragmented Genes that code for
    Kappa light-chain locus
  • 1 Set of Fragmented Genes that code for 1 heavy-chain locus

All of these Fragmented Genes are brought together to transcribe an mRNA and translate a protein

59
Q

What does a multivalent antigen do

A

Has multiple different kinds of epitopes that kind bind many different kinds of antibodies

60
Q

Serum Levels of each Ig Isotype

A

IgG, then IgA and IgM, then small amounts of IgE

61
Q

What are the regions on a polypeptide chain of an antibody

A

Variable Region (N-terminus)
Constant Region (Remainder)

62
Q

Which isotypes are co-expressed

A

IgM and IgD through differential mRNA splicing of the primary RNA gene

63
Q

Lamda vs Kappa vs Heavy (Signal Sequence)
- Also how many variable sections

A

Lambda
7-23-9-9-12-7
30 Variable

Kappa
7-12-9-9-23-7
40 Variable

7-23-9-9-12-7-7-12-9-9-23-7
65 Variable

64
Q

What happens when a B-Cell’s immunoglobulin binds to an antigen

A

It differentiates into a antibody-secreting plasma cell

65
Q

What is the most common isotype switch

A

Switch to IgG, which is secreted as a monomer

66
Q

What determines the strength of an epitope binding (Shape)

A

The shape that an epitope binds to can vary
- Pocket (Tightly bound)
- Groove (Loosely bound)
- Surface (Very Loosely bound)

67
Q

What is Glycosylation
- Where does it occur?

A

Attachment of sugars to specific amino acid residues
- Occurs in the Endoplasmic Reticulum and the Golgi Apparatus

Two types:
- N-Glycosylation (Asn)
- O-Glycosylation (Ser, Thr)

PHARM 310 (8 decks)

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