Lectin Receptors Flashcards
What are the main types of glycosylation?
N and O
What does glycosylation do?
Uses sugar to control proper folding of the protein
Where does glycosylation occur?
In the Golgi
What are many lysosomal hydrolyses labelled with and why?
Mannose, you dont want them hanging around so you label them and they are removed
What is the difference between mannosylation and salicylation?
Mannosylation is normally a sign of something going wrong
Salicylation is fine
What do pathogens try to do to beta glucan?
They try to mask it because it is a sign of non-self
What are the 3 groups of vertebrate lectins?
- intracellular
- located at the plasma membrane
- secreted
What does the intracellular M family of lectins do?
Control folding of proteins
What are siglecs a subgroup of?
The immunoglobulin superfamily
What are siglecs predominant ligands?
Sialylated glycan
What does ITIM stand for?
Immunoreceptor tyrosine-based inhibitory motif
What do ITIMs do?
Tend to dampen immune responses as a whole
Do most siglecs have ITIM or ITAM as the common signalling motif?
ITIM but some can engage adaptor molecules that have an ITAM
What happens if you put sialic acid on antigens and feed them to antigen presenting cells?
They get tolerance, so engaging this receptor that binds sialic acid, you are inducing acceptance of that cell
What is the largest and most diverse of the lectin families found in animals?
C-type lectins
What is a C-type lectin-like domain (CTLD)?
A characteristic fold formed by disulfide linkages between highly conserved cysteine residues
Why do many C type lectins have to have multi MERS?
Because by providing several low affinity interactions, you are increasing the avidity
What does changing glycosylation do in c type lectins?
Changes binding capacity of the receptor
What residues are in the primary Ca2+ binding site that bind mannose?
Residues EPN
What will every protein binding mannose tend to bind to as well?
Glucose and N-acetyl glucosamine
Why would you not expect Dectin-1 to signal very well?
Because it has an ITAM-like motif
What does the ITAM-like motif of dectin-1 do?
Binds many sugars that are clustered, many molecules affecting one come together and now you have signalling
What is the receptor chain for Mincle?
An Fc receptor gamma chain
What does the Fc gamma receptor chain do?
Can signal and provide an activating signal because they engage the receptor. The adaptor itself doesn’t have a signalling motif, then when you engage with the adaptor it can then signal
What does an ITAM-coupled motif mean?
Will engage an adaptor that has a motif
How can syk be recruited?
In different ways through an adaptor molecule that has the ITAM motif, through a receptor that has an ITAM motif or another way
What does receptor engagement of inhibitory c-type lectins lead to?
IITIM tyrosine phosphorylation by Src kinases
1) phosphorylated ITIM leads to recruitment and activation of protein tyrosine phosphatase such as SHP-1 and SHP-2
2) desphosphorylation of substrates regulated by immunoreceptors leading to the inhibition of cellular activation
What is the central complex for signalling in C-type lectins?
CARD9, BCL10, MALT1
What does the CARD9 complex activate?
NFkappaB
What does DC-sign activate?
RAF1 which is a MAP kinase - this is an immunomodulation
What type of molecule is DC-SIGN?
Type 2 membrane molecule with a cytoplasmic domain containing an internalisation motif, a transmembrane domain, stalk region and CRD
What does DC-SIGN form?
Tetramers
What does DC-SIGN recognise glycans through?
CRD
What type of c-type lectin-like domain does DC-SIGN have?
EPN motif and has two Ca2+ coordination sites
What is DC-SIGN expressed by?
Immature DCs in peripheral tissues and mature DCs in lymphoid tissues
What is expression of DC-SIGN regulated by?
IL-4
What is DC-SIGN function?
Enhances antigen internalisation and presentation by DCs to T cells
What are the consequences of DC-SIGN engagement?
Major role as immunomodulation
DC-SIGN alone does not initiate changes in DC activation or cytokine secretion, but can shape immune responses by modulating the signaling elicited by other PRRs
What type of receptor is the mannose receptor?
An endocytic receptor
What does mannose receptor bind?
Fucose, mannose or N-acetyl glucosamine
How many domains does the mannose receptor have?
3 different domains
What up-regulates mannose receptors?
IL-4, IL-13 and IL-10
What cells express mannose receptors?
Macrophages, selected DC populations, lymphatic and hepatic endothelia
What is the main function of mannose receptor?
Invovled in healing immune response, is there to mop up after resolution of inflammation
What happens when mannose receptor binds allergens?
Promotes Th2 responses
What type of protein is dectin-1?
Type II transmembrane protein
What are the domains of Dectin-1?
C-type lectin-like domain
A stalk and transmembrane region
Cytoplasmic tail containing ITAM-like motif
What is dentin-1 predominantly expressed on?
Myeloid cells, monocytes, macrophages, dendritic cells and neutrophils
What does Dectin-1 recognise?
Beta-1,3 and Beta-1,6 linked glucans (but not those containing solely Beta-1,6 linkages)
What does the affinity of Dectin-1 interactions depend on
Is influenced by degree of branching and polymer length
What type of immunity does Dectin-1 have a focus on?
Anti fungal
What happens for signalling of Dectin-1 upon ligand binding?
The ITAM-like motif becomes tyrosine phpshprylated and is sufficient to recruit Syk kinase. Requirement for receptor dimerisation
What happens once receptor dimerisation of Dectin-1 occurs?
Induces a signalling pathway common to all CLRs -
> activation of CARD9, Bcl10 and Malt1 complex
> leads to NFkappaB activation
> syk can also activate non-canonical NFkappaB activation pathway through NIK
What can dectin-1 induce syk-independent signalling thorugh?
RAF-1
What does cross-talk between Dectin-1 and TLR2 do?
Promotes production of pro inflammatory cytokines
What does Dectin-1 signalling with TLR9 do?
Inhibits signalling to TLR9
What does dectin-2 bind to?
High mannose structures
What does dectin-2 signal to?
Fc gamma common chain
What adaptor does dectin-2 require?
An adaptor with an ITAM motif
Does dectin-2 trigger the same or different signalling pathwya to dectin-1?
Same type of signalling pathway
What type of response does dectin-2 promote?
Th17 response
What does mingle bind?
Instead of high mannose, it binds glycolipids
What receptor is mingle linked to?
Fc gamma common receptor
What does MICL stand for?
Myeloid inhibitory C-type lectin-like receptor
What controls tissue damage responses?
DNGR-1
What is exposed when tissue damage occurs?
F-actin
