Toll Like Receptors

1. Toll-like receptors (TLRs) *found in macrophages, dendritic cells and some epithelial cells
*13 different TLRs, but all have VERY similar structures = REDUNDANCY
-genes often duplicated as a mistake that occurs in normal DNA replication
-this allows for the evolution of new proteins with new functions in a signaling pathway
A. Transmembrane proteins
~Have extracellular, membrane, and intracellular domains
~Signal transduction, get signal — conformation change of transmembrane protein leads to change in intracellular region in protein, which leads to new interaction with cytoplasmic proteins which in turn leads to a new gene expression of inflammatory cytokine genes
*Extracellular domain:
-interacts with microbe specific molecular motifs
-"leucine-rich repeats" (LRRs) comprise most of TLR EC domain
*Intracellular domain:
-conformational change when target binds to EC domain of TLR, this change in interactions w/other intracellular proteins—transcription of inflammatory cytokine genes
B. Recognition of conserved microbial targets

i. Bacterial Cell envelope features
*TLR 4 -LPS
*TLR 1 & TLR 2-lipoproteins
*TLR 5-flagellin
ii. Parasite features
*TLR 2 & TLR 6-fungal cell wall carbs
*TLR 2 & TLR 11-eukarotic parasite membranes
iii. Microbial Nucleic Acid Motifs
*TLR 3- ds RNA
*TLR 9-CpG motifs (unmethylated)
*TLR 7 & TLR 8-ss RNA (from viruses)
C. Accessory proteins assist TLRs
i. TLR4 can only bind to Lipid A of LPS IF MD2 is bound to TLR4
ii. This works best if Lipid A presented by CD14(cell surface proteins found on macrophages and dendritic
cells, granulocytes)
iii. LBP, LPS-binding Proteins, attaches to free lipid A, presents it to CD14-TLR 4-MD2
iv. Lipid A would be more present when bacteria dies!! Than when its alive
d. Cell surface and vacuolar TLRs
i. Lecuine repeats are inside of vacuoles where things such as dsRNA would be located because only come
from break down of the virus
II. Nucleotide-oligomerization domain proteins (NODs)
i. Very conserved!
ii. Upon rec. of intraceullar peptidoglycan -> transcription etc. of inflammatory cytokines
b. Cytoplasmic proteins: aka intracellular proteins
c. Recognition of peptidoglycan: (conserved components)
1. Bacterial invasion of cells -> NOD 1 activation of transcription etc of inflam. cytokines by host cells
ii. NOD 1: recognizes peptidoglycan component from gm(-): (invaded these cells)
1. Found in many cell types (in us)
iii. NOD 2: recognizes peptidoglycan component found in cell wall of both gm (-) and gm (+) (probably
engulfed)
1. Mainly found in macrophages and dendritic cells
d. Bacterial invasion of cells
i. Activate NF-kappa-B(transcriptional activator which leads to production of -> IL-1β & TNF gene
expression activates caspaces process IL-1β (at high levels triggers apoptosis)
e. Activate NF-kappa-B and caspaces
f. Diseases associated with NODs

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