Human FcRn (GST-Fusion)

Human neonatal Fc receptor (FcRn) was named for its role in transferring IgG molecules across placenta to the fetus. Structurally, it is distinct from the classical IgG receptors for its similarity to the MHC class I instead of the Ig superfamily (IgSF) molecules. Binding of FcRn to IgG protects the latter from being proteolytically attacked by the endocytic lysosomal enzymes. The preservation of the antibody molecules by FcRn is central to the homeostasis of the antibody levels in circulation. 

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Quick Spec

Description

The first quarter of antibodies contain variable regions capable of recognizing a great variety of antigens. The second half of antibodies contains the Fc domain with limited variation and is critical for bringing together the bound-antigen with cellular effector functions. The IgG Fc receptors which mediate the effector functions are expressing on leukocytes and are composed of three major classes: FcγR1 (CD64), FcγRII (CD32) and FcγRIII (CD16).

In human, the latter two contain subgroups: FcγRIIA and FcγRIIB, as well as FcγRIIIA and FcγRIIIB. Structurally, each FcγR contains the α chain which is a member of Ig superfamily and is directly interacting with the Ig Fc. Of importance, the α chain of FcγRII receptors contains the signalling motif of either ITAM (immunoreceptor tyrosine-based activation motif) or ITIM (immunoreceptor tyrosine-based inhibition motif). In contract, the ITAM or ITIM motif is absence from FcγRI and FcγRIII receptors, instead the signalling transduction of these receptor is mediated through the accessory proteins, γγ homodimer or γζ heterodimer which contains the ITAM motif.

FcγRIIB is the only FcγR contains the ITIM, hence the sole inhibitory receptor. For binding to human IgG1, FcγRI exhibits a high affinity in the nM (10-8-10-9) range and can bind monomeric IgG. In contrast, the FcγRII and FcγRIII interacts with monomeric IgG with a much weaker affinity at the tenths of uM (10-7) range.

Amino Acid Sequence

AESHLSLLYHLTAVSSPAPGTPAFWVSGWLGPQQYLSYNSLRGEAEPCGAWVWENQVSWYWEKETTDLRI
KEKLFLEAFKALGGKGPYTLQGLLGCELGPDNTSVPTAKFALNGEEFMNFDLKQGTWGGDWPEALAISQR
WQQQDKAANKELTFLLFSCPHRLREHLERGRGNLEWKEPPSMRLKARPSSPGFSVLTCSAFSFYPPELQL
RFLRNGLAAGTGQGDFGPNSDGSFHASSSLTVKSGDEHHYCCIVQHAGLAQPLRVELESPAKSSGHHHHH
HMSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSM
AIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCH
KTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQAT
FGGGDHPPKSDIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKD
WSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM

References

1. Pyzik M, Kozicky LK, Gandhi AK, Blumberg RS. The therapeutic age of the neonatal Fc receptor. Nat Rev Immunol. 2023;23(7):415-32. Epub 20230201. doi: 10.1038/s41577-022-00821-1. PubMed PMID: 36726033; PubMed Central PMCID: PMC9891766.

2. Gessner JE, Heiken H, Tamm A, Schmidt RE. (1998) The IgG Fc receptor family. Ann Hematol. 76231-248.

3. Maenaka K, van der Merwe PA, Stuart DI, Jones EY, Sondermann P. (2001) The human low affinity Fcgamma receptors IIa, IIb, and III bind IgG with fast kinetics and distinct thermodynamic properties. J Biol Chem. 276:44898-44904.

4. Mechetina LV, Najakshin AM, Alabyev BY, Chikaev NA, Taranin AV. (2002) Identification of CD16-2, a novel mouse receptor homologous to CD16/Fc gamma RIII. Immunogenetics. 54:463-468.

5. Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. (2005) FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity 23:41-51.