Fc receptors oct 28 2009 extra reading on web
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Fc Receptors Oct. 28, 2009 Extra reading on web PowerPoint PPT Presentation


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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

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Fc Receptors Oct. 28, 2009 Extra reading on web

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Fc ReceptorsOct. 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

  • 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


FceRI


Initial model for the FceRI

1982


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


ITAM Motif


(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)


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


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


KAR is NK activating receptor


Examples of proteins that

have an ITIM in cytoplasm


“ITIMs control ITAMs”


Mechanism of SHIP – cleaves 5’ phosphate from PI3,4,5-P3 – then

IP3 cannot be made – blocking calcium release.


Fc receptor cluster in mouse and human


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


IgA Transport


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