Notes 3.4

I. Toll-like Receptors
a. transmembrane proteins
• 3 domains:
o Intracellular, extracellular and transmembrane
 Extracellular domain interacts w/ microbe-specific molecular motifs
 “leucine-rich repeats” (LRRS) comprise most of TLR extracellular domain
 Intracellular domain: conformational change when target binds to extracellular domain of TLR which change interactions w/ other intracellular proteins
• Transcription of inflammatory cytokine genes
b. Recognition of conserved microbial targets
i. Bacterial cell envelope features
• TLR4-LPS
• TLR1 & TLR2
-lipoproteins
• TLR5-flagellin
ii. Parasite features
• TLR2 & TLR6
-fungal cell wall carbohydrates
• TLR2-recognize molecules specific to certain kinds of eukaryotic parasite membranes
• TLR11
-recognize molecules specific to certain kinds of eukaryotic parasite membranes
iii. Microbial nucleic acid motifs
• TLR3-dsRNA
• TLR9
-CpG motifs (unmethylated)
• TLR7 & TLR8—-ssRNA only from viruses
• 13 different TLRs, but all have very similar structures (redundancy)
o Genes often duplicated as a mistake that occurs normal DNA replication
o This allows for the evolution of new proteins, w/ new functions in a signaling cascade
c. Accessory proteins assist TLRs
• TLR4 can only bind to Lipid A of LPS if MD2 is bound to TLR4
o This works best if Lipid A presented by CD14
a. CD14 found on macrophages, dendritic cells, granulocytes
• LBP, LPS-binding protein, attaches to free lipid A, presents it to CD14-TLR4-MD2
d. Cell surface and vacuolar TLRs
• Can either be localized to the surface of a macrophage/dendritic cell or in vacuoles on the inside of a macrophage/dendritic cell
II. Nucleotide-oligomerization domain proteins (NODs)
• In cytoplasm
• Recognize peptidoglycan
• Very conserved
• Upon recognizing intracellular peptidoglycan, transcription etc. of inflammatory cytokines
a. Cytoplasmic proteins
b. Recognition of peptidoglycan
1. NOD1
• peptidoglycan component from gm(-)
• **found in many cell types
2. NOD2
• Peptidoglycan component from both gm(+) and gm(-)
• **mainly in macrophages, dendritic cells
c. Bacterial invasion of cells
• NOD1 activation of transcription etc. of inflammatory cytokines by host cell
d. Activate NF-kappa-B and caspaces
• Leads to IL-1β & TNF gene expression
• Activate caspaces—process IL-1β
1. at high levels, trigger apoptosis

Similarities btw TLRs and NODs: bind various microbial motifs.
Differences: NODS intracellular, TLRs extracellular

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