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52 Cards in this Set
- Front
- Back
In the case of a viral infection, what neutralizes the extracellular virus particles? What produces this?
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Antibodies (made by B cells)
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In the case of a viral infection, what eliminates the source of the virus?
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T cell response
(Humoral B cell response cannot do this) |
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Where are viral proteins made?
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Within the host cell, by the host's own protein synthesis machinery
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Why must an effective immune system test both vacuolar and cytoplasmic compartments?
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- Viral fragments (red) are in cytoplasm
- Bacterial fragments (green) are in vacuolar compartments |
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Through what process do viral and bacterial proteins get degraded?
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Routine protein turnover - all proteins in a cell (both cellular and foreign) are degraded to fragments/peptides via this process
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What happens to the peptide fragments of viral and bacterial origin after being degraded by routine protein turnover?
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Peptide fragments are presented to T cells on Class I (viral) or Class II (bacterial) MHC molecules = Antigen Presentation
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What is the inside of a vacuole equivalent to?
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Outside of the cell
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What is the primary difference between Class I MHC and Class II MHC molecules?
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- Class I - sample inside of a cell (cytoplasm)
- Class II - sample outside of a cell/vacuoles |
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What is the process of a molecule being presented on a Class I MHC antigen?
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1. Proteins must be tagged for destruction
2. Proteolysis must occur to generate peptides of appropriate size 3. Peptides must be delivered to class I MHC molecules 4. Peptides must bind to class I MHC molecules 5. Peptides must be displayed to T cells in context of class I MHC molecules |
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How are proteins tagged for proteolysis?
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- Ubiqutin (small 8 kDa protein) added to protein destined for degradation (on Lysine residues)
- Forms a Ub chain (polyubiquitination) |
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How are peptides generated?
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- Protein that is labeled w/ Ubiquitin is recognized by Proteasome
- Proteasome cuts up protein to release peptides |
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What are some characteristics of the peptides that are presented on Class I MHC molecules?
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- 9 peptides long
- End w/ a hydrophobic residue (L, I, V, F) |
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If a cell is infected with a virus, how does it enrich for peptides that are suitable for loading onto class I MHC molecules?
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- Proteasomes have 3 types of protease activity that are suitable for producing peptides that are presented on class I MHC molecules
- Chymotrypsin-like proteases, Trypsin-like proteases, and Caspase-like proteases - Chymotrypsin-like proteases cleave proteins so that they end w/ a hydrophobic residue (L, F, I, V) |
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Which type of proteases cleave proteins to generate peptides that end with hydrophobic residues? What is the significance of this?
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Chymotrypsin-like proteases (end w/ L, F, I, or V) - these peptides are suitable for binding to Class I MHC molecules
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What must happen to a protein before it can be processed by the proteasome? Why?
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- Ubiquitin must be removed by isopeptidases
- Protein must be unfolded by unfoldases - The diameter of the center of the proteasome is only 13A (so can't fit a folded protein w/ ubiqutin on it) |
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What size of peptides does the proteasome generate?
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4-20 AA residues
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What happens to peptides after they are cleaved by the proteasome?
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TAP: Transporter associated w/ Antigen Processing transports peptides into the ER
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What is the preferred substrate of the TAP (Transporter associated w/ Antigen Processing)?
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- Only peptides
- Favors peptides ending w/ L, I, V, or M (hydrophobic) - 6-15 AA residues |
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What are the molecular sieves that limit the size of peptides that are presented onto Class I MHC molecules?
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- Proteolysis by proteasomes generates peptides 4-20 residues
- TAP transporter selects for subset ending w/ L, I, V, or M that are 6-15 residues long - Binding to class I MHC molecule has strict size restrictions of 8-10 residues (image shows that many are 9 AA long) |
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Which proteins help keep the TAP transporter in close proximity to the Class I MHC molecule? Why?
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- Tapasin and light chain β2m
- Makes sure that Class I MHC molecules are close to the incoming peptides |
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When does this process happen?
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At all times, regardless of whether foreign proteins are present
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What happens when a virus infects a cell?
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1. Protein tagged for destruction (ubiquitin)
2. Proteolysis (peptides ending in L, I, V, or M) 3. Delivery of peptide (selection for L, I, V, or M enders) 4. Binding of peptide (chaperone-mediated) 5. Transport to cell surface and presentation to T cells (which proceed to kill the cell presenting the peptide) |
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What is the structure of the Class I MHC molecule?
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- Heavy chain makes peptide-binding cleft on its own (α1, α2, and α3)
- Light chain (β2-microglobulin) is much smaller - Peptide is critical to structure (without it molecule falls apart) |
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In which kind of MHC molecule does a single heavy chain form the entire peptide-binding cleft?
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Class I MHC
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What is the structure of the Class II MHC molecule?
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- 2 Heavy chains contribute equally to peptide-binding cleft (α1/α2 and β1/β2)
- No light chains - Peptide is critical to structure (without it molecule falls apart) |
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In which kind of MHC molecule do two heavy chains form the peptide-binding cleft?
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Class II MHC
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What happens if there is no peptide bound to a MHC molecule?
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MHC molecules fall apart, therefore the peptide is considered a subunit of the MHC molecule
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What secondary structures form the peptide binding cleft of MHC Class I molecules?
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α1 and α2 both contribute α helices and β pleated sheets (both from heavy chain)
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What secondary structures form the peptide binding cleft of MHC Class II molecules?
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- α1 and β1 each contribute α helices and β pleated sheets
- α1 and β1 are from separate heavy chains |
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Class I MHC molecules hold what length of peptides in their binding cleft?
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8-10 residues
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Class II MHC molecules hold what length of peptides in their binding cleft?
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10-16 residues, but can be longer, up to 30+
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How does tagging of proteins differ for Class I vs Class II MHC molecules?
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- Class I - proteins must be tagged (ubiquitination)
- Class II - no tagging of proteins |
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How does delivery of peptides differ for Class I vs Class II MHC molecules?
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- Class I - Peptides must be delivered to MHC molecules
- Class II - No topological barriers, delivery not an issue |
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How does the location of binding of peptides to MHC Class I vs Class II molecules differ?
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- Class I - in ER
- Class II - in endocytic compartment (not ER) |
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Class I vs Class II MHC molecules bind to which T cells?
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- Class I - CD8 T cells
- Class II - CD4 T cells |
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In the Class II MHC molecule pathway, how do you know what is going to be lysed?
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Anything that is delivered to the lysosome - does not have to be tagged
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How are antigens lysed into peptides for the Class II pathway?
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Lysosomal Proteases (Cathepsins - cystein proteases)
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What is the concentration of Cathepsin / Lysosomal proteases in the lysosome?
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On the order of mM (this is very concentrated)
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What is the pH in a lysosome?
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pH = ~5
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How do Class II MHC molecules get into the lysosome (where they load peptides)?
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- Start at ER
- Pass through Golgi - Lysosome (where they load peptides) - Plasma membrane |
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How do you prevent peptides in ER destined for Class I molecules from binding to class II molecules?
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Invariant chain (Ii) sits in peptide groove and blocks binding of peptides in ER
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What is Invariant chain (Ii)?
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- Scaffold, stabilizer
- Barrier to peptides in ER (sits in peptide groove) - Contains zip code to MIIC (MHC Class II Compartment) |
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What part of the Invariant chain (Ii) peptide sends the MHC Class II molecules to the lysosome? What is the name of this compartment?
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- LL sorting signal (two lysine residues)
- Sends MHC Class II to MHC Class II compartment (MIIC) |
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What is the structure of Invariant Chain (Ii)?
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Trimer w/ 3 class II molecules and 3 invariant chains
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How do you remove the Invariant Chain (Ii) from the MHC class II groove?
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- Cathepsin initially cleaves Ii to leave a fragment bound to the molecule and the mebrane
- Further cleavage leaves peptide fragment, CLIP in groove - HLA-DM catalyzes exchange of CLIP and antigenic peptide |
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What is the function of HLA-DM?
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Catalyzes exchange of CLIP (peptide remaining in Class II MHC groove) for an antigenic peptide
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Is the groove of a Class II MHC molecule usually empty or full?
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Usually full - only empty when HLA-DM catalyzes the removal of CLIP (before binding of antigenic peptide)
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Why must a peptide almost always be found in the groove of the Class II MHC molecule?
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Without the peptide in the groove the Class II molecule is destabilized (black), it unfolds, and is destroyed by proteases in the lysosome
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Can self-peptides be presented by Class II MHC molecules?
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Yes
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What are the specialized antigen presenting cells for Class II MHC molecules?
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- B cells
- Dendritic cells - Macrophages |
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On what kind of cells are Class I MHC molecules expressed?
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All nucleated cells
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On what kind of cells are Class II MHC molecules expressed?
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Only on specialized antigen presenting cells (B cells, Dendritic cells, and Macrophages)
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