Download Toll-like receptor

Toll-like receptor
Isella Claudio
Tlr family
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14 elements recognised in mammalians so far; 10 of these are found in human genome
scattered on all the cromosome.
The protein encoded is 90, 115 KDa.
The Toll receptor is a type I transmembrane receptor, evolutionarily conserved, and
homologs are found in insects, plants and mammals.
The N extracellular domain of Toll receptors contains leucinerich repeat (LRR).
The citoplasmatic domain shows striking homology with that of IL-Rs, and is referred to
as Toll/IL-1R (TIR) domain.
TLR are found on cellular surface or in the endosomial compartments (TLR3 TLR7
TLR9)
First experiment on drosofila. In drosofila TLR4 is involved in the enbryonic
development ancient family. Different function
Structure of TLR
The Toll Like Receptor molucels presents two
domains of particular interest.
TIR
Toll, isoleucine receptor domain, is in the
citoplasmatic region
• around 150 aa, it’s found both in isoleucin
1 receptor, IL-1r, and in Toll Like receptor.
• Not casually these receptors share the
same signaling pathway.
• The TIR domain can interact with other TIR
domains omo and etero oligomers with
other TLRs and adaptator proteins.
Disulfide bridge in Cys around 700 allows
the interaction beetween domains.
• In the BB loops there is the conserved
region, in corrispondence of protein
surface.
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LRR
Leucine repeated region; XLXXLXLXX,
highly repeated (21 in tlr4.).
• It is found in the ectoplasmatic region of
the receptor in solenoid disposition, with
a β-sheet base (16β sheet).
• Two capping region in the N e C
direction.
• Insert sequence in TLR 7, 8, 9. The
function for this reagion has not yet been
found
• The surface of this receptor is 10 time
greater than TCR o BCR.
• Two functional regions responsible for
some interaction
TLR1
TLR2
TLR3
TLR4
TLR5
TLR6
TLR7
TLR8
TLR9
ligando
Triacil peptides
Soluble factor
lipoproteine/lipopeptidi
peptidoglicani
acidi lipoteicoici
lipoarabinmannosio
glicoinossitolfosfolipidi
zymosan
Heat Shock protein 70
Double stranded RNA
LPS
taxolo
proteine dell'envelop
HEAT shock protein 60
HEAT shock protein 70
dominio A della fibronectina
oligosaccaride dell'acido ialuronico
fibrinogeno
flagellina
lipopetidi diacetilati
acidi lipoteicoici
zimosan
imidazoquinoline
loxoribine
single strand RNA
imidazolo
single strand RNA
CpG-containing DNA
origine
batteri
neisseria meningitis
vari patogeni
gram +
gram +
micobatteri
fungi
Host
Virus
gram plant
TLR ligands
A big range of molecules from
different filia and pathogens can
be recognised
Even ligand form the
host can bound the
receptor
host
host
For each receptor at least one ligand
host
host
is found .
batteri
How can this receptor bind all this
micoplasma
kinds of molecules?
gram +
fungi
synthetic compound
synthetic compound
virus
virus
batteri e virus
Cis interaction between TLR
Peptidoglicano
Diacetilated
peptidoglicans
lipopeptides
Triacetilated
peptidoglicans
Heteromeric interaction
Ozinsky et al TLR2 anbd TLR6 together
can recognize PAMPS that couldn't be
recognised alone.
The same happens for TLR1 & TLR2.
In this way it is possible to enlarge the
range of the PAMPs recognized by
TLR. Combination of TLR
Proinflammatory
cytokines
TLR6
TLR2
TLR1
TLR4 recognition machinery
LBS
TLR4 drosofila
LPS
TLR4
MD-2
Interaction with other molecules
CD14
MD-2
LBP
Recruits of the TLR4 in omodimeric form,
and activation of the pathway that leads
to tumor necrosis factor
human?
T
I
R
T
I
R
Some experiments suggest that MD-2 can
act as regulator in the recognition of
particular patterns
Other interacting molecules
Integrin
FcγR
CD11b, CD18, or CR3, receptor for C3
seems can interact with LPS. This is
still uncertain, however, the level of
the immunological response seems
to depend from this class of integrin
This receptor enhances the ability of
phagocitic cells to interact with
antigen opsonized with IgG.
Cooperation with TLR encreases
the level of IL-10, and
downregulate IL-12.
Dectin-1
A lection PRR, that recognize fungal βglucans. Higher level of Dectin-1
leads to an increased response to
zymosan and other fungal
molecules
Scavenger receptor
The scavenger receptor are a family
of structural unrelated PRR implied
in the uptake of low-density
lipoproteins. It was shown that
treating cells with TLR’s ligand
induces expression of SR.
MyD88’s Pathway
T T
I I
R R
IRAK
4
DD
IRAK
1
TRAF6
IRA
K4
TAB2
IRAK
2
IRAK2
TRAF6
IRAK1
TAB TA
2
K1
My
D8
8
IKK
MKK4/7
IKB
P
IKB
Nucleo
NF-KB
JNK
NFKB
proinflammatory cytokine
transcription
JNK
Other adaptative molecules
TLR3 doesnt depend on MyD88.
Cells without MyD88 don’t lose the
expression of cytokines, only the cynetic
changes.
TIRAP = MAL
Adaptative molecules in MyD88 pathway.
It’s necessary for TLR2 and TLR4
activity
TRAM
TRIF
Adapter protein in charge of the MyD88
indipenent pathway. Lack of TRIF
abrogate TLR3 response, INF type I,
and reduce the response to treatment
with LPS on TLR4 cells.
It leads to the trascription of interferon α and
β.
Adaptative protein, associated with TRIF in
TLR4, but not in other signal
transduction
The C terminus is responsible for the signal
transduction.
SARM
It can activate NF-kB in TLR4 stimulation
even if it’s not known how.
Orthologue in caernobia elegans, it can
activate antimicrobial peptides, but is not
related with TLR.
TLR 5 7 9
TLR1/6
L
R
R
TLR4
TLR2
L
R
R
L
R
R
L
R
R
TLR3
L
R
R
L
R
R
Inflammatory response, mediated by
My
D8
8
T
R
I
F
cytokines: IL-1b,TTNF-a, IL-2, IL-6, GM-CSF,
IL-12
T
T
T (p40),
TNF-a, IL-4,
I My
D8
IL-5,R IFN-g
8
A
P
My
D8
8
I
R
A
P
R R
A I
M F
C hemokines: IL-8, RANTES, MIP-1a, MCP-1, eotassina,
IP-10
Adhesion molecules: ICAM-1, VCAM-1, E-selectin
IRAK
complex
Enzimes: iNOS, Cox2, cPLA2, 5-LO
?
immunoreceptor: MHC, b2-microglobulin
Type I interferon
IKK-ε
TBK
IRF3
NF-KB
NF-KB
proinflammatory cytokine
transcription
IRF3
IRF3
Type I INTERFERON
genes
Negative regulation
IRAK M
MyD88
It’s expressed only on macrophage and
monocyte.
It associates with the IRAK complex,
inhibiting the separation from the DD
domain of MyD88
Alternative splicing form, that can’t bind
IRAK4. It blocks the signal transduction
SOCS1
Can regulate the cytokines pathway. The
absence of this protein leads to
hyperstimution after treatment with CpG
DNA or LPS.
SIGIRR
Immunoglubulin transmembrane with TIR
domain, can interact with MyD88
IRAK1 and TRAF6.
ST2
TIR domain. It seizes MyD88.
Reference
C R Biol. 2004 Jun;327(6):581-9
Functions of toll-like receptors: lessons from KO mice.
Akira S, Takeda K.
Nat Rev Immunol. 2004 Jul;4(7):499-511
Toll-like receptor signalling.
Akira S, Takeda K.
C R Biol. 2004 Jun;327(6):571-80.
Forward genetic dissection of afferent immunity: the role of TIR adapter proteins in innate and adaptive immune responses.
Beutler B, Hoebe K, Shamel L.
Trends Immunol. 2003 Oct;24(10):528-33.
Leucine-rich repeats and pathogen recognition in Toll-like receptors.
Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM.
Immunology. 2004 Aug;112(4):521-30
The potential for Toll-like receptors to collaborate with other innate immune receptors.
Mukhopadhyay S, Herre J, Brown GD, Gordon S.
Nature. 2000 Nov 2;408(6808):111-5
Structural basis for signal transduction by the Toll/interleukin-1 receptor domains.
Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley JL, Tong L.