3 - Recognition and Response Flashcards
Receptor-ligand binding
A receptor molecule attaches to its ligand by the same types of noncovalent chemical linkages that enzymes use to bind their substrates (hydrogen and ionic bonds, hydrophobic and van del Waals interaction). The key to the receptor-ligand interaction is that the sum of the bonding interactions holds the two interacting surfaces together with sufficient binding energy for sufficient time to allow a molecular signal to be received by the cell.
Receptor-Ligand interactions strenght
Dissociation constant (K_d) provides a quantitative measure of the strength of the ligand binding. Lower K_d = higher affinity. if [ligand]=K_d, 50% of the ligand is bound to the receptor
K_d= ([S]*[L])/[SL] S= free receptor sites L= free ligand SL = receptor-ligand pair
Interactions between receptors and ligands can be multivalent
BCR have more than one ligand-binding site per molecule, aka multivalent.
benefit: non-covalent binding interactions are reversible; ligand spends some time “on” and some time “off”. If there are multiple binding sites, it is less likely that the ligand will be “off” all the receptor sites simultaneously (i nwhich case the ligand can be released)
Avidity = overall strength of the collective binding interactions that occur duting multivalent binding.
monovalent receptors can cluster around multivalent ligands to avoid the ligand leaving.
Combinational expression of protein chains can increase ligand-binding diversity
By using different combinations of protein chains, the immune system can increase the variety of different receptor binding sites.
The combination of one receptor chain with multiple different partners
Adaptive immune receptor genes undergo rearrangement in individual lymphocytes
recombination of C and V genes, in addition to one C can combine with multiple different Vs in different cells (after priliferation after successful C?) = a gigantic variability
The DNA seq that the BCR and TCR are made up of are short (they make up the heavy and light chains). random combinations of these on different cells, in addition to random combinations of the protein chains (heavy and light chains).
Varying expression of receptors, include one interleukin example from lymphocytes
receptor expression patterns may change when a cell is activated, making it more or less responsive to particular signals
Most resting (non-Ag-activated) lymphocytes express a heterodimeric (two-chain) form of the IL-2 receptor, with intermediate affinity. This means that for physiological cytokine concentrations, IL-2 will not bind. Upon activation of the lymphocyte, the expression of a thirs chain of the IL-2 receptor increases, increasing the affinity for IL-2 and thus allows binding.
Local concentrations of ligands may be extremely high during cell-cell interactions
Cell-cell interactions allow the directional release of ligands, creating locally high concentrations and increasing signal strength.
Many immune receptors include immunoglobulin domains
The immunoglobulin superfamily of proteins includes BCRs, TCRs, adhesion molecules, and other receptors that function in the immune system.
CDRs = complementary-determining regions = the part of the BCR that makes contact with the Ag.
Immune Ag receptors locations
Immune receptors may be located on the plasma membrane, on intracellular membranes, in the cytosol, or even floating around in tissue fluids.
the locations are more variable in the innate than adaptive system
BCRs can be secreted. Its then called an antibody. Consists of two identical heacy chains and two identical light chains
BCR vs Ab
same specificity
B cell can make both soluble and membrane-bound Ig-receptors, encoded by the same gene and sharing a binding site.
Difference in membrane-bound and soluble form:
soluble have a hydrophobic AA seq of various lengths at the C-terminus. In membrane-bound, these are replaced by three regions:
1) extracellular, hydrophilig “spacer” seq (ca 26 AA)
2) hydrophobic transmembrane segments (25 AA)
3) very short cytoplasmic tail
In resting form, only membrane-bound are made. Upon activation, both are made.
3D structure of Ab
2 Light + 2 HEavy (identical)
disulfide bonds
2 Ag binding sites
L = two immunoglobulin domains, H = 4 or 5
Ag-binding site is made up by V_L and V_H.
CDR = complementary-determining regions.
two major classes of L-chain = (kappa + lambda).
the heavy chain = 5 seq types: gamma, alhpa, mu, epsilon and delta (GAMED).
Immature B cell: membrane bound AgR (BCR)
Mature, unstimulated B cells: IgM and IgD.
The expression of the others (IgG, IgA and IgE) requires an addtional and irreversible DNA recombination step (later chapter)
BRC coreceptors
CD21 = coreceptor, participates in the Ag-binding activity of the BCR complex.
binds to C3d on the Ag
cooperative binding occurs when Ag are first identified as foreign by the innate immune system (innate immune system covalently binds a C3d protein fragment to the pathogen). The CD21 specifically binds to C3d. The Ag is then bound directly through the BCR and indirectly via CD21.
BCR signal transduction mediators
ITAM = immunoreceptor tyrosine-based activation motifs. Short seq of AA.
The BCR complex includes IGalpha and IGbeta, ITAM-bearing proteins that transduce signals from Ag-binding to the interior of the cell
TCR structure
Ag-recgonizing (variable region)
“height-gaining” region (constant region)
transmembrane region
to chains (alpha+ beta, or gamma+delta)
C+V are held together by disulfide bonds between Cys-residues.
three CDRs (like BCRs) in their V domains.
gamma-delta TCR have more limited Ag-binding site diversity than BCR and alpha-beta-TCR.
TCR coreceptors
CD4 and CD8 are the only two accessory molecules that have direct involvement in Ag-rec. CD28 is also a coreceptor that decides activation, but is not directly involved with Ag-binding
CD4 = monomeric membrane glycoprotein. 4 extracellular Ig-like domains (D_1 -> D_4), a hydrophobic transmembrane region, and a long sytoplasmic tail.
CD8 is a disulfude-linked alpha-beta heterodimeric or alpha-alpha homodimeric glycoprotein. Each chain consists of a single, extracellular, Ig-like domain, a stalk region, a transmembrane region, and a cytoplasmic tail.
CD4 binds MCH II, CD8 binds MHCI
Activation of T cells requires CD28 coreceptor to engage its ligand, CD80 or CD 86, on the APC.
CD28 is requires so the TCR (which can’t distinguish between self and non-self) doesn’t bind self-peptides on MCH.
