Ch03-+Recognition+and+response

Receptor-ligand binding occurs via multiple noncovalent bonds.
- Each individual bond may be weak, but collectively they provide a strong binding affinity.
- Many such bonds occur between receptors and ligands, delivering great cumulative bond strength.
Dissociation constant (Kd): A measure of the strength of ligand binding.

Antigen-immune system receptor interactions are enhanced by co-receptor binding.
- Co-receptor interactions are separate receptor-ligand interactions near the initial interaction.
- Often, a single type of interaction is insufficient for activation events.
- Co-receptor binding can provide a secondary signaling interaction that promotes cell activation.

Receptor-antigen interactions are typically multivalent.
- Multivalency: Increases avidity (overall strength) of interactions.
- Individual interactions have affinity (the strength of a pairing), determined by both the association rate constant (Ka) and the dissociation constant (Kd).
- Avidity is the cumulative strength from multiple interactions, meaning an interaction may exhibit weak affinity yet high avidity overall.

Ligand-receptor binding induces various changes in the receptor:
- Conformational change: Alteration in shape and structure.
- Dimerization/clustering: Formation of receptor dimers or clusters.
- Location change in the membrane: Movement of the receptor within the cell membrane.
- Covalent modification: Alterations through covalent bonds.
Receptor alterations initiate cascades of intracellular events such as:
- Activation of enzymes.
- Changes in intracellular localization of molecules.

Ligand binding enhances receptor aggregation, increasing Kd for further ligand binding.
Cell-cell interactions depend on binding affinity to sustain interactions over time, facilitating:
- Signal transduction.
- Cytokine signal exchange.
- Cytoskeletal reorganization upon prolonged binding.

Immune receptors typically carry immunoglobulin domains.
They can be classified as:
- Transmembrane: Embedded in the cell membrane.
- Cytosolic: Present within the cytosol.
- Secreted: Released from the cell, as seen in immunoglobulins lacking the transmembrane segment (produced via alternative RNA splicing).
B-cell Receptor (BCR): Contains an antibody with specific binding.
T-cell Receptor (TCR): Specific for peptides derived from antigen-presenting cells (APC) that have been processed and are presented on major histocompatibility complex (MHC) molecules.
CD4 and CD8: T-cell co-receptors that identify distinct T-cell functional subsets.

Antibodies are quaternary proteins composed of:
- Two identical heavy chains.
- Two identical light chains.
Antigen specificity arises from the variable regions of light and heavy chains.
Effector functions (e.g., phagocytosis, complement fixation) result from interactions of the constant regions of the heavy chain.

Antibodies feature three hypervariable regions of amino acids within the variable heavy (VH) and variable light (VL) regions:
- These regions form the antibody's combining site.
- Designated as complementarity-determining regions (CDR1, CDR2, CDR3).
- Framework regions consist of invariant amino acids essential to the folding of CDRs into the combining site.

Two identical antigen-binding sites allow binding of two identical antigens, enhancing avidity.
Light chains can be either lambda (λ) or kappa (κ), with no significant functional differences.
Heavy chain isotypes determine antibody classes: g, m, d, a, e (IgG, IgM, IgD, IgA, IgE).
IgG antibodies have a molecular weight of approximately 150 kDa, with each antibody capable of binding to two antigen molecules.

Five classes/isotypes of antibodies, differentiated by the amino acid sequence of the heavy chain, each fulfilling unique functions in immune responses.

BCR complexes with signal transduction molecules such as:
- Igα and Igβ: Transmit signals via immunoreceptor tyrosine-based activation motifs (ITAMs).
- CD19, CD81, CD21: Transmit and relay signals to the cell interior.

The T-cell receptor (TCR) structurally resembles immunoglobulin domains.
- Composed of two subunits (α and β), each with constant and variable regions.
- Variable regions encompass three CDRs, forming the peptide-binding site.
- Constant regions include transmembrane segments.
Types of TCR: αβ and γδ, showcasing diverse antigen-binding characteristics.

TCR identifies and binds to both antigen-derived peptides and the MHC to which these peptides are bound.
- Peptide sources can be derived from proteins processed endogenously or exogenously.

The TCR complexes with coreceptors essential for antigen recognition:
- CD3: Contains ITAMs that transmit signals to the cell.
- CD4 and CD8: Increase peptide binding avidity by the TCR.
- CD28: Engages CD80/CD86 on APCs, fully activating naive T cells.

PAMPs: Expressed on innate immune cells and recognized uniformly across different bacteria.
PAMP receptors are non-clonally distributed but equally expressed on similar cell types:
- Integral membrane proteins or intracellular proteins.
PAMPs represent repetitive motifs of bacteria, yeast, and parasites.

TLR (Toll-like receptor): Localized in the plasma membrane and endosomes; recognizes microbial carbohydrates and cytokine production leading to inflammation.
CLR (C-type lectin receptor): Plasma membrane receptor; recognizes carbohydrate components from fungi, viruses, etc., facilitating phagocytosis and inflammatory responses.
RLR (Retinoic acid-inducible gene-I (RIG-I)-like receptor): Cytosolic receptor that recognizes viral RNA, inducing interferons and cytokines.
NLR (Nucleotide oligomerization domain (NOD)-like receptor): Cytosolic receptor identifying