Chapter Three Receptors And Signaling : B And T-cell Receptors Flashcards

(104 cards)

0
Q

Antigens

A

Foreign molecules that signal the presence of no self entities to immune system

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1
Q

Receptor protein

A

One of major routes by which a cell interprets its surroundings is through the binding of signaling molecules, or ligands, to these proteins

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2
Q

Cytokines

A

Small molecules that communicate among various populations of immune cells

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3
Q

Chemokines

A

Specialized cytokines that induce chemo-attraction or -repulsion

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4
Q

Cellular signal

A

Any event that instructs the cell to change its metabolic or proliferative state

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5
Q

How are signals usually generated

A

By the binding of a ligand to a complementary cell-bound receptor

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6
Q

What types of ligands are there

A

Soluble molecule, or peptide, carbohydrate or lipid

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7
Q

How does ligand travel

A

Through bloodstream or lymphatics

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8
Q

What kind of molecular change can a ligand induce in a receptor

A

Conformation change
Dimerization or clustering
Change in location in membrane
Covalent modification

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9
Q

What do ligand caused receptor alterations set off

A

Cascades of intracellular events like activation of enzymes, changes in intracellular location of important molecules

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10
Q

What is usual end result of cellular signaling

A

Change in transcriptional program of target cell

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11
Q

Hoe does ligand bind to receptor

A

By noncovalent chemical linkages

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12
Q

Association constant

A

The ratio of k_1/k_-1, or association rate constant/dissociation rate constant. A measure of affinity of the receptor ligand pair. The relationship between the concentration of reaction product and the product of the concentration of reactants. (Ka). The higher the Ka, the higher the affinity of the interaction.

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13
Q

Dissociation constant, Kd

A

Reciprocal of association constant. The lower the Ke, the higher the affinity of the interaction.

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14
Q

What are multi alert receptors

A

They have more than one ligand binding site per molecule

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15
Q

What is the benefit of multivalency

A

Noncovalent binding interactions are inherently reversible. The ligand spends some of its time on receptor and some of its time off. When more than one binding site is involved, it is less likely that all of the receptor sites will be simultaneously in the off state so that ligand is released.

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16
Q

Avidity

A

Overall strength of the collective binding interactions that occur during multi alert binding. This can be accomplished with a molecule with multiple binding sites or a receptor that can create a cluster in membrane,

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17
Q

How do we measure affinity of receptor-ligand interactions

A

Techniques such as equilibrium dialysis or surface plasmon resonance.

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18
Q

Why is it important that receptors are in low affinity form and are expressed on as needed basis

A

By waiting before expressing high affinity cytokines receptors, lymphocyte conserves energy and prevents accidental initiation immune response to an irrelevant gene,

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19
Q

How are cytokines released exactly where they are needed

A

Antigen receptor signaling can induce redistribution of the microtubules organizing center (MTOC) within the activated T cell. This causes redistribution of secretory organelles within th T cell cytoplasm, so that cytokines made by the T cell are secreted in the direction of thr T cell receptor, which in in turn is binding to the antigen-presenting cell

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20
Q

Vectorial redistribution of the secretory apparatus

A

Process that helps cytokines be secreted directly into space between. Activated T cell and antigen presenting cell.

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21
Q

Where are cytokines most concentrated

A

At cellular interfaces. So, where two cells meet.

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22
Q

Signal transduction

A

Molecular route by which a ligand receptor interaction is translated into a biochemical change within an affected cell.

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23
Q

Upstream components of a signaling pathway

A

Components closest to the receptor

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24
Downstream components of signaling pathway
Those closest to the effector molecules that determine the outcome of the pathway
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Common features of signaling pathways
Conformational changes in or clustering of the receptor Some receptors require receptor associated molecules to signal cell activation Ligand-induced receptor clustering can alter receptor location Tyrosine phosphorylation is an early step in many signaling pathways Adapter proteins gather members of signaling pathways Phosphorylation on serine and threonine residues Phosphorylation of membrane phospholipids Signal induced PIP2 breakdown by PLC causes an increase in cytoplasmic calcium concentration Ubiquitination may inhibit or enhance signal transduction
26
What does conformation change in receptor result in
Receptor Dimerization. In cytoplasmic regions of receptors, there is a lot of tyrosine kinase activity that results in reciprocal phosphorylation of the cytoplasmic region of each of the receptor molecules by its dimerizarion
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What is clustering
When receptors aggregate into multimedia complexes and move into a specialized membrane region.
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What happens when receptor doesn't have inducible enzyme activities built into it
Receptor needs help from intracellular receptor associated molecules to bring about signal transduction.
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Immuno-receptor tyrosine activation motif (ITAM)
Recurrent sequence motifs found on many signaling proteins that become phosphorylated following signal transduction through the associated receptor. This allows docking of adapter molecules that facilitate initiation of signaling cascade.
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Lipid rafts
Specialized regions of the lymphocyte membrane into which receptors move after attaching to ligand
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Tyrosine phosphorylation event is important because
It can initiate a signaling pathway
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Src-family kinases
Family of enzymes to which many of tyrosine kinases that initiate BCR and TCR activation belong
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Which kinases are critical to T cell activation
Lck and Fyn
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Which kinases are critical to B cell activation
Lyn, Fyn, and Blk
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In what two ways are Src-family tyrosine kinases regulated
The enzymes exist in a closed conformation when they are inactive A phosphorylated tyrosine inside is bound to an internal SH2 domain
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How can tyrosine phosphorylation bring about changes in a signaling pathway
Can induce a conformational change | Can permit other proteins to bind
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Adapter proteins
Mediate reversible interactions between proteins caused by signaling events
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Protein scaffold
Structural framework of adapter proteins for interaction among members of a signaling cascade
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Common domains in adapter proteins functioning in immune system
SH2 SH3 PH
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SH2 domain
Binds to phosphorylated tyrosine residues
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SH3 domain
Binds to clusters of pro line residues
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Pleckstrin homologue domain (PH)
Binds to phosphatidyl inositol triphosphate in the plasma membrane
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What does binding of adapter protein do
Induce conformational changes or | Up cover one or more protein domains with specific affinity for other proteins
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Homophobic interaction
Interaction between identical domains
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Heterotypicq interactions
Interactions between different domains
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When does phosphorylation on serine and threonine residues happen
Later in signaling event. Serves many purposes.
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Phosphatidyl inositol bis-phosphate (PIP2)
Phospholipid component of the inner face od eukaryotic plasma membranes, actively participates in cell signaling
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Phosphatidyl inositol-3-kinase (PI3) kinase
Enzyme activated during the course of cell signaling. Phosphorylates PIP2 to form phosphatidyl inositol tris-phosphate
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phosphatidyl inositol tris-phosphate (PIP3)
Remains in membrane and serves as binding site for proteins bearing Pleckstrin homology domains.
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Phospho lipase C (PLC)
Activated upon antigen signaling of lymphocytes. Hydrolyzes PIP2' cleaving inositol trisphosphate (Ip3) from the dyacylglyerol backbone
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Diacylglycerol (DAG)
Remains in membrane and binds and activates a number of importsnt signaling enzymes
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IP3
Released into cytoplasm. Interacts with specific receptors on surface of endo plasmid reticulum vesicles, inducing release of stored calcium ions into cytoplasm
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Calmodulin
Calcium binding protein
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Ehat ahopens when calcium ion levels start to drop after binding
Calcium ion channel proteins assemble at membrane. Allow calcium to flood in from cytoplasm to complete activation of calcium regulated proteins
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Store operated calcium channel proteins
Channels that form on membrane to let calcium ino in. Prohibited in the presence of high intracellular calcium.
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How is Ubiquitin used
Binds to lysine residues. Tags a protein for destruction or can serve as activation signal.
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Three signaling pathways
PLC pathway RAs/MAP kinase cascade PKC
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PLC pathway
``` Tyrosine phosphorylation of ITAM Localization of adapter protein LAT LAT phosphorylated and PLC binds to adapter protein and membrane. Tyrosine phosphorylation of PLC Cleavage to IP3 and DAG ```
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What is release of calcium ions for by IP3
Calmodulin binds to four calcium ions. Its conformation is altered Binds and activates phosphatase calcineurin
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What does calcineurin do
Dephosphorylated transcription factor NFAT, which induces a conformational change, which reveals a nuclear localization sequence, which directs NFAT to enter nucleus and activate transcription of a number of important T cell target genes.
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What does DAG do in membrane
Binds and activates enzymes if the protein kinase C family. These kinases are serine/threonine kinases are active in a variety of signLing pathways
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RAs signaling pathway
RAs is a monomeric GTP-binding protein. When it binds to GTP, its conformation changes into an active state Hydrolyzes GTP to GDP intrinsically, but can't be active in a GDP state, so needs to be kept in GTP state.
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How to maintain RAs in GTP bound state
Guanine nucleotide exchange factors (GEFs) activate RAs by inducing it to release GDP and accept GTP GTPase activation protein (GAPs) inhibits protein's activity by stimulating Ras's intrinsic ability to hydrolyze bound GTP
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How is RAs pathway initiated
DAG binds and activates RAs-GRP, an adapter protein that recruits GEF SOS. SOS binds to RAs and induces it to bind to GTP, at which point RAs gains its ability bind and activate the first member of a cascade of serine/threonine kinase enzymes that phosphorylate and activate each other
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Mitogen activated protein kinase (MAP) cascade
Cascade of kinase enzymes
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NF-kB
Belongs to a family of heterotrimeric transcription factors and each diner activates its own repertoire of promoters
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Inhibitor of NFkB
Holds NFkB heterodimers in cytoplasm of resting cells by binding
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ikB kinase
Phosphorylates NFkB when cell is activated
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What are antibodies made of
Multiple immunoglobulin domains
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Antibody common structure
Four polypeptide chains, two identical light chains and two identical heavy chains. Each light chain is bound to its partner heavy chain by a disulfide bond between corresponding cysteine residues, as well as by noncovalent interactions between Vh and Vl domains and Ch and Cl domains.
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Hinge region
Flexible area that joins compact regions of antibody. Susceptible to cleavage by papain.
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Fab regions
Fragments of antibody that have antigen binding specificity
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Fc region
Non antigen binding portion of antibody
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Two major classes of antibody light chains
Kappa and lambda chains
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Variable of light chain
N terminal of light chain
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Constant of light chain
Less variable part of sequence
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Complementarity determining regions (CDRs)
Hyper variable regions that interact with bound antigens
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Five major classes of antibody heavy chains
Mu, delta, gamma, epsilon, alpha
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Isotype
Each different heavy chain constant region
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What does isotype of heavy chain determine
Its class
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Mu isotype heavy chains
IgM class
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Delta heavy chain
IgD class
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Gamma heavy chain
IgG class
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Epsilon heavy chain
IgE
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Alpha heavy chain
IgA
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Length of constant regions of heavy chains
Mu and epsilon, 440 amino acids | Gamma, delta and alpha, 330 amino acids
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Sub isotypes
Sub classification of heavy chains
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Subclasses
Subclassification of antibodies
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Plasmacytomas
Tumors of plasma cells, the end stage cell of. B cell differentiation, located in bone marrow
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Multiple myeloma
Metastasized plasmacytoma
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What do plasmacytomas and myeloma a do
Secrete large amounts of monoclonal antibodies into serum and tissue, which can be purified in large quantities
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Bence-Jones proteins
Homogenous light chains secreted by myeloma rumors
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Antigenic determinant
Region of an antigen that makes contact with the antigen combining region on an antibody
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Anti isotype antibodies
Directed against antigenic determinants present on constant region of one particular heavy chain or light chain class of antibody
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Allotypes
Alternative allergic forms of same isotype
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Allotypic determinants
Determinants vary by just a few residues
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Anti allotype antibodies
Generated by immunizing an individual of one species with antibodies derived from a second animal of the same species bearing an alternative form of the particular r immunoglobulin gene
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Anti idiotypic antibodies
Antibodies directed against the antigen binding site of a particular antibody
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Anti Fab and anti Fc antibodies
Made by immunizing a different species of animal from that which provided the antibody fragments
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Ch1 and Cl domains
Serve to extend antigen binding arms of the antibody molecule
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Hinge region purpose
Rich in pro line residues, flexible, can assume a wide variety if angles with respect to one another, which facilitates efficient antigen binding. Has cysteine that participate in heavy chain Dimerization.
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Ch2 and Ch3 domains
Domains are separated from their partner domains by oligosaccharide side chains that prevent heavy chains from getting close, making pair more accessible to aqueous environment
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Carboxy terminal domains
Has hydrophilic amino acid sequence of various lengths. Sequences depend developmental stage.