Fc Receptors Oct. 28, 2009 Extra reading on web

1. Fc ReceptorsOct. 28, 2009 Extra reading on web Daniel Conrad 423 MSB, 828-2311 I. CD23

2. CD23 – Member of the C-type animal lectin family

3. Trimeric structure means Avidity is important in Binding.

4. 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

5. 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

6. FceRI

7. Initial model for the FceRI 1982

8. Current Model for the FceRI Shows interaction of a-chain with IgE

9. 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

10. Depending on where it is expressed – can exist as a,b,g2 or as a,g2.

11. Cyrstal structure of complex has revealed site of interaction.

12. FceRI is part of a family of Multichain immune recognition Receptors (MIRRs) that use an ITAM activation scenario

13. ITAM Motif

14. (aggregation) ITAM

16. 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)

17. PH is Pleckstrin Homology domain – binds PI 3,4,5 P3

18. 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

21. Summary of FcR structure showing ITAMs or ITIMs in cytoplasm

22. Cartoon showing glycerol-phosphotidyl inositol (GPI) linked protein PLD and PLC are enzymes that cleave at positions indicated

23. KAR is NK activating receptor

30. Examples of proteins that have an ITIM in cytoplasm

32. “ITIMs control ITAMs”

35. Mechanism of SHIP – cleaves 5’ phosphate from PI3,4,5-P3 – then IP3 cannot be made – blocking calcium release.

37. Fc receptor cluster in mouse and human

39. 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

41. FcγRIV • Expressed in mouse – binds IgG2a/2b best • Expressed on macrophages and dendritic cells • Opsonic Fc receptor – especially for these subclasses of IgG

42. IgA Transport