430 likes | 562 Views
Fc Receptors Oct. 28, 2009 Extra reading on web. Daniel Conrad 423 MSB, 828-2311 I. CD23. CD23 – Member of the C-type animal lectin family. Trimeric structure means Avidity is important in Binding. CD23 Summary. Only Fc receptor that with no relationship to Ig superfamily
E N D
Fc ReceptorsOct. 28, 2009 Extra reading on web Daniel Conrad 423 MSB, 828-2311 I. CD23
Trimeric structure means Avidity is important in Binding.
CD23 Summary • Only Fc receptor that with no relationship to Ig superfamily • Two isoforms exist – differ only in first six amino acids (in cytoplasm) • Cleaved form loses trimeric structure – only interacts with IgE with low affinity • Other ligands as well – CD21, CD11/CD18
CD23 Function • Isotype control – IgE synthesis • Antigen presentation – IgE complexes are internalized and degraded – peptides are then associated with class II MHC • B cell growth and differentiation – in association with IL-1
Current Model for the FceRI Shows interaction of a-chain with IgE
FceRI composition • Three proteins required for expression in rodent – though a,g2 works in human • alpha-chain binds IgE • Beta – amplifies signal – binds src related kinase (lyn). • Gamma – ITAMS are phosphorylated and interact with syk – this same gamma chain also is associated with FcgRI, RIIIA
Depending on where it is expressed – can exist as a,b,g2 or as a,g2.
Cyrstal structure of complex has revealed site of interaction.
FceRI is part of a family of Multichain immune recognition Receptors (MIRRs) that use an ITAM activation scenario
(aggregation) ITAM
Receptor activates PTK either directly or indirectly – recruits syk family – activates PI3K which phos. PI3,4,5P3 – this recruits PLCg and Tec family – which produces IP3 – this releases intracellular Ca and opens CRAC (Ca release activated channels) (Cell 94:5-8, 1998 – reference for above figure if needed)
FceRI Mechanism • ITAMs become phosphorylated (lyn) and bind syk, which then becomes activated • Syk and Fyn activate– PI3 kinase – produces PtdIns-3,4,5 P3 • Binds PLCg and Tec family member (btk) • IP3 is produced – causing release of intracellular calcium and influx of calcium (CRAC) • Syk also activates vav – via SLP -- and eventual gene transcription
Summary of FcR structure showing ITAMs or ITIMs in cytoplasm
Cartoon showing glycerol-phosphotidyl inositol (GPI) linked protein PLD and PLC are enzymes that cleave at positions indicated
Examples of proteins that have an ITIM in cytoplasm
Mechanism of SHIP – cleaves 5’ phosphate from PI3,4,5-P3 – then IP3 cannot be made – blocking calcium release.
Evidence that another Fc Receptor was present • FcRγ KO was more severe than FcγRI or FcγRIII α-chain. • This was especially true if antibody class was IgG2a/IgG2b and the effector cell was myeloid in nature. • Fcrl3 – 60% Id with FcγRIII α-chain. • Charged aa in transmembrane domain
FcγRIV • Expressed in mouse – binds IgG2a/2b best • Expressed on macrophages and dendritic cells • Opsonic Fc receptor – especially for these subclasses of IgG